Hematologic autoimmune disorders in the course of COVID-19: a systematic review of reported cases

ABSTRACT

Objective

As COVID-19 is a new emerging disease, the hematological/immunological changes that develop in the infected patients remain unknown. This study aims to systematically review the hematologic autoimmune complications in these patients.

Method

Data from three online databases including Medline (via PubMed), Scopus and Web of Science were searched on 19 December 2020, and after excluding duplicate, irrelevant and inappropriate records, eligible documents were identified. Afterwards, information such as patients’ history, presentations, paraclinical data, treatment course and outcome were extracted from the records.

Results

A total of 58 documents were considered to be eligible for data extraction which described 94 patients with COVID-19 who developed hematologic autoimmune disorder in their course of infection. Of these patients with COVID-19, the most common hematologic autoimmune disorder was immune thrombocytopenic purpura (55 cases) followed by autoimmune hemolytic anemia (22 cases). Other hematologic autoimmune disorders include antiphospholipid syndrome, thrombotic thrombocytopenic purpura, Evans syndrome and autoimmune neutropenia.

Conclusion

The current study would help us to always consider an autoimmune etiology for cases with abnormal hematologic finding which further lead to an appropriate treatment of the patients, especially when the symptoms present in about 1–2 weeks after the first manifestation of the infection symptoms. Maybe, at least in this pandemic, it should be recommended to evaluate patients with unexpected and unexplained decrease in their hemoglobulin or platelet count for COVID-19. Another challenging issue is the treatment options. Given the multiorgan involvement and multifaceted nature of the infection, an individualized approach should be taken for each patient.

KEYWORDS:

• Hematologic autoimmune disorders
• COVID-19
• SARS-CoV-2
• Thrombosis
• Autoimmunity
• Hemolytic anemia
• Thrombocytopena
• Steroids

Introduction

Late in 2019, a novel viral strain from Coronaviridae family was isolated in the throat culture of a series of patients complained of influenza-like manifestations. This newly emerged strain was subsequently named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. Due to its high primary attack rate, extensive containment measures including universal lockdowns and social distancing were imposed to impede the spread [2]. However, despite these preventive measures, the virus is rapidly spreading through the world turning it from a public health emergency of international concern into a pandemic, declared by World Health Organization (WHO) on 11 March 2020 [3].

While SARS-CoV-2 mainly targets the respiratory tract, with respiratory failure and acute respiratory distress syndrome as the leading cause of mortality among the afflicted patients, extra-respiratory systems’ manifestations are also frequently observed [4]. The typical clinical manifestations of coronavirus disease 2019 (COVID-19) include fever, dry cough, fatigue, sore throat, malaise and myalgia. Furthermore, there are other less common symptoms such as headache, dizziness, diarrhea and nausea and vomiting [4,5].

Recently, an increasing number of studies have demonstrated that SARS-CoV-2 infection could result in alteration in immune system functions [6]. These alterations could range from an inappropriate immune response and abnormal cytokine/chemokine production to immune system hyperactivation and dramatic increase in immune-inflammatory parameters. These vigorous immune responses could lead to autoimmunity and cytokine storm [7]. Besides, researches have reported several cases of patients with COVID-19, among whom autoimmune events were developed such as vasculitis, Guillain–Barré syndrome, etc. [8]. These findings indicate that SARS-cov-2 infection may be associated with the induction of autoimmune disorders. Among these autoimmune manifestations, several hematologic autoimmune disorders have been also reported and showed that could complicate the management and be in association with outcome in patients with COVID-19 [9–12]; however, they are less paid attention to. As COVID-19 is a new emerging disease, little is known about these immunological changes that occur in the afflicted patient. Given this, we aimed to systematically review hematologic autoimmune disorders reported in patients with SARS-CoV-2 to shed light on this era for better management of patients.

Method

Search sources and strategies

In the current study, a systematic review for relevant records about hematologic autoimmune events developing in the course of SARS-CoV-2 infection was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [13]. Data were gathered from three different online databases including Medline (via PubMed), Scopus and Web of Science. The search has been conducted by the third author in 16 August 2020 and updated in 19 December. In order not to miss any data, a broad search strategy was developed with a combination of key terms of both coronavirus and hematologic autoimmune disorders. The keywords used for coronavirus were COVID-19, coronavirus, SARS-CoV-2 and 2019-nCoV. Furthermore, the following keywords were considered for hematologic autoimmune disorders: autoimmune, autoimmune anemia, autoimmune hemolytic anemia, hemolytic anemia, cold agglutinin, AIHA, pernicious anemia, immune thrombocytopenia, immune thrombocytopenic purpura, idiopathic thrombocytopenic purpura, ITP, thrombotic thrombocytopenic purpura, TTP, Evans syndrome, autoimmune cytopenia, autoimmune neutropenia, antiphospholipid syndrome, anticardiolipin, Beta-2-glycoprotein, lupus anticoagulant and APS.

Study selection

Six hundred and fifty-three articles in PubMed, 1050 articles in Scopus articles and 494 articles in Web of Sciences were found following the search and then their citations were exported into endnote X9(Clarivate Analytics, USA). At first, duplicate records (678 documents) were removed from the library and afterwards, first screening was conducted by the first and second authors; in this step, titles and abstracts of the records were evaluated in order to remove those which are clearly irrelevant; however, those records which were unclear whether they are eligible for final qualitative analysis or not were kept in the study for subsequent screening (Figure 1); in the second round of the screening process, full texts of the records were evaluated for relevancy. Records from papers with any design or methodology which did not describe the cases who developed hematologic autoimmune disorders including their presentations, their paraclinical workups, their treatment course, etc. were excluded in the second screening round. In this study, not only case reports and case series but also letters or commentaries that included information of SARS-CoV-2-infected patients with hematologic autoimmune disorders were considered eligible. Besides, not only documents of the patients with new onset of hematologic autoimmune disorders, but also documents that reported a relapse or flare of a chronic hematologic autoimmune disorder were included in the qualitative synthesis. There were no restrictions based on the country of origin or the language used in the articles. Besides, both published papers and those that are ahead of print were considered for data extraction.

Figure 1. PRISMA flowchart of the current systematic review process.

Data extraction

An Excel spreadsheet was created to extract the following data: study title, first author, access date, type of study, history of the patient, the clinical symptoms and signs the patient presented with, patient’s paraclinical information, the hematologic complication observed in the patient, the treatment course including for both hematologic disorder and SARS-CoV-2 infection and the patient’s outcome. Among patients’ paraclinical workups, only those helpful for diagnosis of the hematologic disorder the patients afflicted to were gathered from the selected records.

Results

A total of 94 patients with SARS-CoV-2 infection who developed hematologic autoimmune disorders in their course of infection were included in the final analysis. Male and female patients constituted an almost equal proportion of the study cases, 47 and 44 cases, respectively. The gender status of three cases of a study was not identified in the document [14]. The study cases had a wide age range from 2 years to 94 years with a median age of 60 and the mean age of 56 ± 18.5. The elder population constitute the majority of cases with 48.9% (46 cases). There were only three pediatric cases and these three patients were all afflicted to idiopathic thrombocytopenic purpura (ITP). A majority of cases had comorbidities (69 percent); however, 14 out of 29 remaining cases were described in a study in which the underlying disorders of the patients were not reported [15]. The most common presentation in these cases was fever reported in 69 (73%) of them, followed by coughing in 56 (59%) and dyspnea in 40 patients (42%).

Among 94 patients, the most common hematologic autoimmune disorder was ITP in 55 cases (58%) followed by autoimmune hemolytic anemia (AIHA) in 22 cases (23%). Other hematologic autoimmune disorders observed in the literature include antiphospholipid syndrome (APLS) in 10 individuals, thrombotic thrombocytopenic purpura (TTP) in 3 individuals, Evans syndrome in 3 individuals and autoimmune neutropenia in one individual (Table 1). The laboratory workups which led to these diagnoses for each case is documented in Supplementary material 1.

Table 1. Autoimmune hematologic complications of SARS-CoV-2 infections.

First author	History of the patient	Clinical presentations	Timing of the hematologic presentations	Autoimmune disorder	Treatment	Outcome
Zagorski et al. [16]	A 46 Y/O female K/C of iron deficiency anemia, asthma, splenectomy and ITP 27 years ago during pregnancy	Fever, dyspnea, muscle aches, lethargy, ill with generalized jaundice, increased work of breathing, no petechiae or rash	Not mentioned	AIHA –cold agglutinin syndrome	–	Deceased within hours of admission
Patil et al. [17]	51 Y/O female K/C of breast ductal carcinoma in situ post-mastectomy on chemoradiation	Fever, dyspnoea, malaise, pain of ribs and back, tachycardia, O2 sat: 88%	Not mentioned	AIHA – cold agglutinin syndrome	HCQ, solumedrol, heparin, folic acid, packed cell transfusion, warm IV fluids	Recovered (Hb became stable at day 2 and patient discharged after more than 4 days)
Capes et al. [18]	62 Y/O smoker male K/C of HTN and oropharyngeal squamous cell carcinoma on chemoradiation	Fever, mild dyspnea with low O2 sat, marked asthenia Acrocyanosis on day 16 of admission	About 1–2 weeks	AIHA – cold agglutinin syndrome	Packed cell transfusion	Recovered (at 6-week follow-up, the patient was slowly recovering from respiratory failure)
Moonla et al. [19]	24 Y/O female	Fever, dyspnea, dry cough	About 3 days	AIHA – cold agglutinin syndrome	HCQ, darunavir/ritonavir azithromycin, favipiravir	Recovered (Hb starts to raise after 2 days and her respiratory condition recovered in 2 weeks)
Maslov et al. [20]	48 Y/O male K/C of essential HTN, T1DM, obesity and end-stage renal disease on peritoneal dialysis	A weeklong history of weakness, anosmia and decreased appetite, O2 sat: 100% After 3 h of admission, his neurological status declined and he was intubated for airway protection and became hypotensive	Not mentioned	AIHA – cold agglutinin syndrome	Packed cell transfusion	Deceased within 48 h after admission
Jensen et al. [21]	1. 70 Y/O male 2. 67 Y/O male	1. Fever, cough, hypoxia 2. Dyspnea	1. More than 2 days 2. Not mentioned	AIHA – cold agglutinin syndrome	1. HCQ, Ceftriaxone, heparin infusion, vasopressors 2. HCQ, Azithromycin, ceftriaxone	1. Complicated course (not much detail on recovery course) 2. Deceased
Huscenot et al. [12]	1. 43 Y/O obese female K/C of untreated multiple sclerosis 2. 63 Y/O male K/C of HTN	1. Fever, dyspnea, cough, diarrhea, asthenia 2. Fever, progressive worsening dyspnea, cough	1. 16 days 2. 20 days	AIHA – cold agglutinin syndrome	1. Ceftriaxone, tazocilline, azithromycin, packed cell transfusion 2. Not mentioned	1. Recovered (Hb started to raise after 1 d) 2. Recovered (Hb started to raise after 1 d and patient discharged on day 15)
Lazarian et al. [22]	1. 61 Y/O male K/C of HTN and CKD 2. 89 Y/O female K/C of HTN, CKD and AF 3. 62 Y/O male K/C of HTN and cirrhosis 4. 69 Y/O obese female 5. 61 Y/O male K/C of HTN, CKD, DM and hypercholesterolemia 6. 61 Y/O male K/C of DM 7. 75 Y/O obese male K/C of cardiopathy, obstructive bronchopneumopathy, hypercholesterolemia	Not mentioned	1. 13 days 2. 7 days 3. 4 days 4. 10 days 5. 11 days 6. 9 days 7. 6 days	AIHA	1. Steroid 2. Steroid 3. Steroid, rituximab 4. Steroid 5. Packed cell 6. Steroid, rituximab 7. Packed cell	1. Recovered 2. Recovered 3. Recovered 4. Recovered 5. Recovered 6. Recovered (failure with steroid and ongoing with rituximab 7. Recovered
Lopez et al. [23]	46 Y/O female K/C of congenital thrombocytopenia not on therapy	Fever, dyspnea, progressive cough, tachycardia, O2 sat: 99%	About 3 days	Warm AIHA	HCQ, patient failed to respond to IVIG but had good response to steroid, packed cell transfusion	Recovered (Hb raised on days 3 of admission after change of IVIG to steroid and patient discharged on day 8)
Hindilerden et al. [11]	56 Y/O male K/C of HTN	Dyspnea, cough, headache, loss of smell, progressive fatigue, jaundice, tachycardia, tachypnea	4 days	AIHA	Favipiravir, patient failed to respond to IVIG but had good response to steroid, packed cell transfusion	Recovered (patient was completely transfusion independent and symptom-free with the resolution of his pneumonia after 8 days of steroid and discharged on day 14)
Jacobs et al. [24]	33 Y/O female K/C of hypothyroidism	Headache for 2 days and family concern for altered mental status, confused, scleral icterus, tachycardia, tachypnea, delayed responses upon questioning and sluggish reactions to verbal commands	Not mentioned	AIHA	Tocilizumab on day 6, steroid, rituximab on day 10, packed cell transfusion	Recovered (Hb raised shortly after steroid administration on day 1 but the level was unstable; following rituximab therapy, Hb began to stabilize and patient was discharged on day 13)
Hernández et al. [25]	Patient K/C of psoriasis	7-day period of fever, asthenia, headache and a syncope episode without loss of consciousness, tachycardia with hemodynamic stability and mucocutaneous pallor	7 days	AIHA	Steroid	Recovered (Hb raised after steroid administration complete recovery of Hb occurred after 2 weeks)
Jawed et al. [26]	In early 50s Y/O male K/C of uncontrolled HTN and obstructive sleep apnea	Coryzal symptoms 2 weeks prior, shortness of breath on mild exertion, diarrhea, mild jaundice yellowish discoloration of eyes, dark urine, an episode of frank per rectum bleeding, high blood pressure, O2 sat: 96%	About 14 days	AIHA	Adenosine (for supraventricular tachycardia), bisoprolol	Recovered (patient discharged on day 33)
D’Aloisio et al. [27]	46 Y/O male K/C of HTN and hereditary spherocytosis	Respiratory failure and unilateral visual loss after a 12-day history of fever, worsening dyspnea and cough Ophthalmoscopy: bilateral retinal hemorrhage with macular involvement	12 days	AIHA- Cold agglutinin syndrome	Chloroquine, packed cell transfusion	Recovered (patient discharged on day 13)
Sereno et al. [28]	58 Y/O smoker male K/C of advanced small cell lung cancer	Fever, cough, chest pain, progressive asthenia, tachypnea	2 days	Possible autoimmune neutropenia due to coronavirus	HCQ, meropenem, dexamethasone, granulocyte colony-stimulating factor	Recovered (respiratory symptoms improved within 3 days and patient discharged on day 15)
Wahlster et al. [29]	17 Y/O male K/C of refractory chronic ITP on eltrombopag and mycophenolate mofetil	Fever, fatigue, emesis, diarrhea, progressive jaundice, marked pallor, tachycardia, tachypnea and hypoxemia	4 days	Evans syndrome	Steroid, packed cell transfusion	Recovered (Hb became stable within 48 h of steroid administration)
Li et al. [30]	39 Y/O male	First admission: fever, chills, dyspnea, hemoptysis, epistaxis, sore throat, productive cough, tachycardia, tachypnea, oral blood blister, hematemesis, melena, hematochezia and no petechiae, ecchymosis or rash Second admission (10 days later, 4 days after first discharge): intermittent fever, cough, extreme weakness, fatigue and no bleeding	About 7 days	Evans syndrome	First admission: proton pump inhibitor, IVIG Second admission: IVIG	Recovered (in first admission that patient had ITP, resolution of bleeding and raise of Plt occurred on day 5 and the patient was discharged on day 6; Hb drop also responded to IVIG in second admission)
Vadlamudi et al. [31]	23 Y/O female gravida 2, para 1, at 38 weeks of pregnancy in active labor	Spontaneous rupture of membranes, contractions, blood-tinged discharge, history of ecchymosis and an episode of epistaxis 2 weeks prior, no pallor, ecchymosis or organomegaly On day 38 of postpartum: chest pain and shortness of breath	Not clear	Evans syndrome	IV iron dextran, IVIG, rituximab, dexamethasone, packed cell and Plt transfusion	Recovered
Zulfiqar et al. [9]	65 Y/O woman K/C of HTN and autoimmune hypothyroidism	On admission: fever, dry cough, fatigue, abdominal discomfort, tachypnea, O2 sat: 89% On day 4: epistaxis and lower extremity purpura On day 9: right frontal headache without fever, vomiting or focal neurologic deficit	8 days	ITP	IV amoxicillin–clavulanic acid, Plt failed to raise in response to IVIG but increased in response to steroid and eltrombopag, Plt transfusion	Recovered (after administration of steroid and eltrombopag at day 9, Plt increase at day 10 and purpura resolved at day 13)
Revuz et al. [32]	1. 57 Y/O female K/C of psoriatic arthritis on adalimumab and methotrexate 2. 76 Y/O male K/C of metastatic bronchiolar adenocarcinoma on carboplatin, pemetrexed and pembrolizumab 3. 39 Y/O male with history of ITP 15 years ago	1. Fever, tachypnea, petechiae on legs and gingival mucosa 2. Fever, slight purpura on legs 3. Fever, cough, arthralgia, body aches, unilateral epistaxis	1. 9 days 2. The lowest Plt at day 11 3. Less than 7 days	ITP	1. IVIG 2. IVIG 3. IVIG	1. Recovered (Plt raised after first dose of IVIG) 2. Recovered (Plt returned to normal in 7 days) 3. Recovered (Plt raised significantly after first dose of IVIG)
Bennett et al. [33]	73 Y/O female K/C of HTN, hyperlipidemia, seasonal allergies	Fever, shortness of breath, headache, fatigue, diarrhea, generalized body aches	Less than 7 days	ITP	HCQ, dexamethasone (without response), IVIG, Plt transfusion	Recovered (Plt had marked response to treatment on day 4 and discharged on day 5)
Bomhof et al. [34]	1. 59 Y/O male K/C of small bowel stage IV neuroendocrine tumor 2. 66 Y/O female K/C of HTN 3. 67 Y/O male K/C of HTN and DM	1. History of cough and fever 10 days before, oral petechiae and skin hematomas 2. History of fever, dyspnea, cough, diarrhea and vomiting 4 weeks ago, petechiae, epistaxis, increased hemorrhoid blood loss 3. Fever, dyspnea, cough	1. 10 days 2. About 4 weeks 3. 21 days	ITP	1. IVIG, dexamethasone, Plt transfusion 2. Patient did not respond to dexamethasone but responded to IVIG, Plt transfusion 3. Plt transfusion	1. Recovered (Plt raised rapidly in response to IVIG but dropped again, then dexamethasone was administrated and significantly increased Plt) 2. Recovered (Plt raised in response to IVIG administration at day 6) 3. Deceased within 24 h of ITP occurrence (due to intracerebral bleeding)
Hindilerden et al. [35]	86 Y/O male K/C of HTN and DM	Fever, dry cough, fatigue, excessive purpuric eruptions and bruising, oral hemorrhagic bullae, tachycardia, O2 sat: 91%	<7 days	ITP	Favipiravir, azithromycin, IVIG, prednisolone	Recovered (Plt responded to treatment and doubled in 2 days and normalized in the 3rd week)
Lorenzo-Villalba1 et al. [36]	1. 66 Y/O male K/C of HTN, DM & liver cirrhosis 2. 57 Y/O female K/C of HTN, thyroidectomy & secondary hypoparathyroidism 3. 79 Y/O male K/C of HTN and a previous episode of transient recovered pancytopenia	1. Fever, progressive shortness of breath, cough, diarrhea, tachycardia, O2 sat: 93%, diminished Breath sounds with rales in left side, facial and trunk erythema, epistaxis 2. Fever, progressive shortness of breath, dry cough, epistaxis, cutaneous purpura on the lower extremities, oral hemorrhagic bubbles, tachycardia, O2 sat: 92%, diminished Breath sounds with rales in left side 3. Fever, dry cough, confusion, falls, cutaneous petechial purpura on the lower limbs, O2 sat: 93%, diminished breath sound with rales in the right pulmonary base	1. 11 days 2. 8 days 3. About 7 days	1. ITP	1. IVIG, eltrombopag 2. IVIG, eltrombopag 3. No IVIG or eltrombopag	1. Recovered (IVIG was discontinued owing to acute heart failure. Eltrombopag then initiated and after 3 days Plt increased and patient discharged on day 15) 2. Recovered (patient was discharged on day 14) 3. Recovered (spontaneously)
Deruelle et al. [37]	41 Y/O obese man K/C of HTN	Fever, dyspnea, cough, tachypnea, O2 sat: 97%	13 days	ITP	Steroid, IVIG	Recovered (IVIG were introduced on day 14 and Plt began rising after 3 days and then fell again on day 19. IVIG was then administered and 2 days later, Plt returned to normal)
Lévesque et al. [38]	53 Y/O male K/C of HTN, DM, dyslipidemia	Abnormal bleeding from the tracheotomy site and the left main stem bronchus during tracheotomy, no skin purpura	20 days	ITP	Antibiotic combination, IVIG, Plt did not rise in response to high-dose dexamethasone and intravenous tranexamic acid but responded to romiplostim and vincristine, packed cell and Plt transfusion	Recovered (the bleeding finally stopped with the high platelet transfusion support within first 5 days but Plt did not rise; Plt started to increase after 6 days of romiplostim)
Merli et al. [39]	37 Y/O female K/C of SLE and chronic ITP secondary to lupus (treated with IVIG)	History of fever, dry cough, anosmia and fatigue 14 days ago, sudden appearance of lower extremities purpura	14 days	ITP	HCQ, lopinavir/ritonavir, methylprednisolone, IVIG	Recovered (Plt gradually increased and the patient was discharged on day 11)
Yang et al. [40]	1. 32 Y/O female 2. 65 Y/O female K/C of HTN and autoimmune hypothyroidism	1. Fever, cough, fatigue, skin petechia mainly on lower extremities 2. Fever, cough, fatigue, abdominal discomfort, tachypnea, O2 sat: 89	1. 13 days 2. 9 days	ITP	1. Lianhua, qingwen, oseltamivir, methylprednisolone, Plt transfusion 2. Steroid, IVIG	1. Recovered (not much detail on recovery course) 2. Unknown
Martincic et al. [41]	48 Y/O obese male K/C of T2DM and obstructive sleep apnea	Fever, progressive dyspnea, cough, headache, muscle soreness, tachycardia, tachypnea, O2 sat: 60% while receiving high flow oxygen via a non-rebreather mask, blood pressure: 163/60 On day 9: macroscopic hematuria, minor bleeding from oral mucosa and blood clots in gastric residual volume On day 12: petechial bleeding on the torso	12 days	ITP	HCQ, lopinavir/ritonavir, tazocin, nadroparin, IVIG, dexamethasone, pooled Plt concentrate transfusion	Recovered (Plt normalized within 3 days and patient discharged on day 23)
Humbert et al. [42]	84 Y/O male K/C of polymyalgia rheumatica and essential tremor	Progressively worsening dyspnea, cough, bilateral crackles on auscultation On day 6: spontaneous macroscopic hematuria and bilateral epistaxis	16 days	ITP	Ceftriaxone, hydrocortisone, prednisolone, IVIG	Recovered (Plt started to increase the day following IVIG and normalized within 1 week)
Pedroso et al. [43]	1. 67 Y/O female K/C of HTN and ischemic stroke 2. 41 Y/O female K/C of T1DM and CKD	1. She was admitted due to traumatic subcapital right femur fracture and planned for surgery. In hospital course: cough, skin blood suffusions on puncture sites 2. Fever, myalgia, odynophagia, bilateral lumbar pain, dysuria and vomiting, minor self-limited hemorrhagic complications on the puncture sites	1. 16 days 2. 13 days	ITP	1. Plt did not respond to sole use of Plt transfusion; then, with steroid, Plt reached normal levels 2. No specific treatment for ITP	1. Recovered (Plt reached normal levels within 5 days; patient discharged on day 48) 2. Recovered (maintained hospitalized for surveillance and spontaneous Plt recovery)
Nesr et al. [44]	34 Y/O pregnant female in second trimester with a past history of ITP	Fever, dry cough, petechiae, gum bleeding	Less than 1 day	ITP	IVIG, prednisolone	Recovered (Plt rapidly raised on day 2 and the patient was discharged that day)
Metallidis et al. [45]	33 Y/O female K/C of T1DM	Low-grade fever, sore throat, mild myalgias, O2 sat: 98%	7 days	ITP	IVIG, dexamethasone	Recovered (Plt rapidly raised following the treatment and patient discharged about 9 days later)
Tsao et al. [46]	10 Y/O female	History of fatigue, non-productive cough and fever in 3 weeks ago, wet purpura in mouth, petechiae on her lower extremities, chest and neck, ecchymosis of popliteal regions and shins	About 20 days	ITP	IVIG, diphenhydramine, acetaminophen	Recovered (patient discharged at day 2 and had telehealth visits; rash and oral lesions improved within 48 h and Plt normalized in 2 weeks)
Tang et al. [47]	Pregnant female at the 41th weeks of pregnancy	Labor contractions, sore throat, O2 sat: 98%, no signs of easily bruising or bleeding	Not mentioned	ITP	IVIG, Plt transfusion	Recovered (Plt responded rapidly within 1 d)
de la Cruz-Benito et al. [14]	1. 94 Y/O patient K/C of HTN, chronic obstructive pulmonary disease and chronic ITP 2. 55 Y/O patient K/C of hyperlipidemia 3. 41 Y/O patient	1. Fever, persistent cough 2. Fever, dyspnea, persistent cough, myalgia/ arthralgia 3. Fever, dyspnea, persistent cough, myalgia/arthralgia, dysgeusia	Not mentioned	1.ITP relapse 2.New ITP 3. New ITP	1. HCQ 2. HCQ, IVIG 3. Steroid	Recovered (All cases had a good response after initial treatment, faster than is typically observed in other newly diagnosed cases. All the patients exhibited a Plt <7 days)
Murt et al. [48]	41 Y/O male	Cough, rhinorrhea, petechial and purpuric rash, nasal bleeding	15 days	ITP	Favipiravir, high-dose dexamethasone, IVIG	Recovered
Levraut et al. [49]	63 Y/O female K/C of autoimmune hypothyroidism and stroke	History of fever, dry cough and headaches in prior weeks, lower limb purpura, bruises of both arms and legs, bilateral crackles at lung bases	26 days	ITP	IVIG	Recovered (Plt started to increase the day following IVIG; patient was discharged on day 7)
Lobos et al. [50]	22 Y/O male	Petechia on extremities, gingival bleeding and buccal hematoma after a dental procedure	No symptoms of infection	ITP	IVIG, Eltrombopag	Recovered (patient discharged on day 6)
Kewan et al. [51]	89 Y/O male K/C of CHF, HTN, T2DM, CKD and AF (on warfarin)	Dyspnea, dry cough, diarrhea, crackles at lung base auscultation	16 days	ITP	HCQ, tazocin, azithromycin, IVIG, dexamethasone, Plt transfusion	Deceased (Plt responded to 2 days treatment course; patient deceased due to his poor condition)
Hayden et al. [52]	51 Y/O female K/C of long-standing SLE (18 years) and APLS, left below-knee amputation complicated by a perioperative cerebrovascular accident	Fever, 1 week hemoptysis, normal O2 sat	Not mentioned	ITP	The patient failed to respond to initial treatment with IVIG, high-dose steroid and Plt transfusion but responded to eltrombopag	Recovered (on day 8, the patient received first dose of eltrombopag and Plt normalized in 4 days; patient discharged on day 13)
Molinaro et al. [53]	19 Y/O female	Afebrile, fatigue, ageusia, normal O2 sat, diffuse purpuric lesions mostly on lower extremities	14 days	ITP	HCQ, antiretroviral agents, methylprednisolone, IVIG,	Recovered (Plt response initiated at day 3 and patient was discharged at day 5)
Mahévas et al. [15]	1. 58 Y/O female 2. 66 Y/O male 3. 62 Y/O female 4. 62 Y/O male 5. 74 Y/O male 6. 63 Y/O male 7. 65 Y/O male 8. 66 Y/O female 9. 79 Y/O female 10. 59 Y/O female 11. 61 Y/O female 12. 69 Y/O female 13. 53 Y/O male 14. 72 Y/O male	1. Fever, cough, purpura, epistaxis, oral hemorrhagic bullae 2. Fever, cough, anosmia, epistaxis 3. Fever, cough 4. Dyspnea 5. Fever, cough, purpura, mucosal bleeding, gastrointestinal bleeding 6. Fever, dyspnea, cough 7. Fever 8. Fever, dyspnea, cough, purpura, epistaxis, intracranial bleeding 9. Fever, dyspnea, cough, purpura 10. Fever, cough, purpura, mucosal bleeding 11. Fever, cough, anosmia, dysgeusia, purpura 12. Fever, dyspnea, cough, purpura, epistaxis, subcutaneous hematoma, gross hematuria 13. Fever, dyspnea, cough, purpura 14. Fever, dyspnea, cough, diarrhea	1. 10 days 2. 13 days 3. 5 days 4. 2 days 5. 12 days 6. 23 days 7. 22 days 8. 8 days 9. 16 days 10. 30 days 11. 25 days 12. 14 days 13. 27 days 14. 15 days	1. ITP 2. ITP 3. ITP 4. ITP+CLL 5. ITP 6. ITP 7. ITP 8. ITP 9. ITP 10. ITP 11. ITP 12. ITP 13. ITP 14. ITP	1. IVIG, eltrombopag 2. IVIG, eltrombopag 3. Prednisolone 4. Prednisolone 5. Prednisolone 6. Prednisolone 7. Dexamethasone 8. Methylprednisolone, IVIG, eltrombopag 9. IVIG 10. IVIG 11. IVIG 12. IVIG, romiplostim 13. IVIG, Prednisolone 14. IVIG	Recovered (significant response in all patient except for patients 3, 7 and 13 that had relapse on day 58, 30 and 35, responsively)
Pascolini et al. [54]	1. 69 Y/O female K/C of recently diagnosed cerebral lymphoma 2. 88 Y/O male K/C of CHF and recent hip replacement 3. 31 Y/O male	1. Admitted for pulmonary embolism while receiving chemotherapy 2. Flare of CHF 3. Fever and dyspnea	1. 7 days 2. Not mentioned 3. Not mentioned	ITP	1. Ceftriaxone, LMWH, dexamethasone 2. Methylprednisolone 3. HCQ, ceftriaxone, Prednisolone, LMWH	Recovered (All cases recovered but there is not much detail about recovery course)
Soares et al. [55]	2 Y/O female	Fever in prior weeks, bruises and petechiae throughout her body	More than 25 days	ITP	IVIG	Recovered (Plt normalized within 5 days after IVIG administration but relapsed on day 40 post-IVIG)
Clerici et al. [56]	64 Y/O male K/C of HTN and DM	Fever, epistaxis, mucocutaneous petechiae, wet purpura, left axillary lymphadenopathy	3 days	ITP+ Hodgkin’s lymphoma	Plt was unresponsive to steroids and IVIG but romiplostim administration increased Plt, Plt pool transfusions and bilateral tranexamic acid-soaked nasal tampons for epistaxis	Recovered (Plt responded to treatment with romiplostim within 1 week)
Kondo et al. [57]	58 Y/O female K/C of long-standing SLE (nearly 20 years) on prednisolone	2 days history of chest discomfort, O2 sat: 95% On day 6: gingival bleeding	2 days	ITP flare	Ciclesonide inhalation, IVIG	Recovered (Plt normalized after 5 days of IVIG)
Hu et al. [58]	72 Y/O female K/C of chronic ITP for 2 years (currently on prednisolone and cyclosporine)	Fever, productive cough	9 days	ITP flare	Arbidol, interferon α, darunavir/cobicistat, Plt failed to respond to IVIG but responded to methylprednisolone, Plt transfusion	Recovered (Plt normalized after 5 days of methylprednisolone administration)
Albiol et al. [59]	57 Y/O female K/C of HTN and breast cancer in complete remission	Fever, dry cough, anosmia, dysgeusia	6 days	TTP	HCQ, lopinavir/ritonavir, azithromycin, Plt did not respond to IVIG and methylprednisolone but did to plasma exchange	Recovered (Plt significantly raised within 24 h of plasma infusion)
Hindilerden et al. [10]	74 Y/O female K/C of HTN	Dry cough, progressive fatigue, pale, slightly subicteric, apathic confusion, fine bibasilar crackles	5 days	TTP	HCQ, favipiravir, azithromycin, plasma exchange, folic acid, aspirin methylprednisolone	Recovered (Plt raised significantly within 3 days of plasma exchange)
Capecchi et al. [60]	55 Y/O female K/C of TTP (caused by bacterial pneumonia thirty yrs. ago, successfully treated at the time with corticosteroids and plasma exchange)	Mild influenza-like symptoms, dyspnea, malaise, fatigue, chest discomfort, agitation and unconsciousness	3 days	TTP relapse	HCQ, ceftriaxone, azithromycin, caplacizumab, methylprednisolone, plasma exchange, aspirin	Recovered (Plt raised 6 h after the first injection of caplacizumab and normalized after 12 days of treatment; patient was discharged on 31)
Sung et al. [61]	49 Y/O obese female	Fever, progressive shortness of breath, cough, myalgia, rhinorrhea, loss of appetite, tachycardia, tachypnea, O2 sat: 87% On day 6: extremities swelling and pain	11 days	APLS	HCQ, ceftriaxone, azithromycin, LMWH	Recovered (after 3 days of anticoagulation and HCQ therapy, she was noted to have significant improvement in respiratory status and swelling of extremities)
Zhang et al. [62]	1. 69 Y/O male K/C of HTN, DM and stroke 2. 65 Y/O female K/C of HTN, DM and coronary artery disease and no history of thrombosis 3. 70 Y/O male K/C of HTN, emphysema, stroke and nasopharyngeal carcinoma	1. Fever, dyspnea, cough, diarrhea, headache, evidence of ischemia in the lower limbs bilaterally as well as in digits two and three of the left hand 2. Fever, dyspnea cough 3. Fever, dyspnea, headache fatigue	1. 18 days 2. 33 days 3. 10 days	APLS	1. Oseltamivir, IVIG 2. Antibiotics 3. Antibiotics, ribavirin, rosuvastatin	Not mentioned
Escher et al. [63]	72 Y/O male	6 days history of fever and respiratory symptoms On day 6: rapid deterioration of clinical condition with development of acute respiratory distress syndrome, acute renal insufficiency and altered mental status	More than 12 days	APLS	Prophylactic dalteparin which was replaced with therapeutic dose of LMWH on day 21	Recovered (not much detain on the recovery course)
Hossri et al. [64]	1. 29 Y/O female K/C of hemoglobin S-C disease 2. 58 Y/O male K/C of dyslipidemia	1. Fever, non-productive cough, vomiting, abdominal pain, generalized myalgia, tachycardia, bibasilar crackles, lethargy, altered mental status, O2 sat: 99% 2. Fever, shortness of breath, non-productive cough, tachycardia, cold left lower extremity with mild pallor and cyanosis with absent dorsalis pedis and posterior tibialis pulses	1. 10 days 2. 15 days	APLS	1. HCQ, tocilizumab, therapeutic heparin 2. HCQ, azithromycin, anakinra, LMWH	Not mentioned
Maria et al. [65]	48 Y/O male K/C of primary APLS (revealed by venous thromboembolic event) treated since 2013 with vitamin K antagonists	Fever, cough, myalgia, mild hypoxemia (pO2: 75 mm Hg), O2 sat: 96% On day 7: sudden abdominal pain (bilateral adrenal glands hemorrhage) On day 12: painful acral ischemic lesions concerning left toes (dorsalis pedis artery occlusion)	12 days	APLS flare	HCQ and azithromycin, VKA switched for LMWH on day 7. On day 12, LMWH was replaced by IV continuous unfractionated heparin (anti-Xa)	Recovered (there was no other clinical or radiological thrombotic event occurred after administration of unfractionated heparin and patient was discharged on day 22)
Cardoso et al. [66]	18 Y/O female K/C of autism spectrum disorder and panic disorder	History of productive fever, dyspnea, cough and malaise in prior weeks, tachypnea, tachycardia, hypotension, hemodynamic collapse and respiratory failure which progressed to cardiac arrest and had a pericardial tamponade drained, severe ventricular dysfunction (EF: 20–25%) and worsening renal function with proteinuria and hematuria requiring hemodialysis, multiple DVT	More than 14 days	SLE and possible APLS	HCQ, ceftazidime, vancomycin, azithromycin, tocilizumab, steroids, plasma exchange, anticoagulation	Deceased (plasmapheresis was discontinued due to a concern of possible removal of antibodies needed for the adaptive response to infection; patient deceased on day 17)
Frankel et al. [67]	66 Y/O female with past history of multiple abortions	Fever, dyspnea, vomiting and nausea, abdominal pain, history of one episode syncope, decreased blood pressure diffuse abdominal tenderness, O2 sat: 94%	5 days	APLS	Steroid	Recovered (patient was discharged on day 11)

AF, atrial fibrillation; AIHA, autoimmune hemolytic anemia; APLS, antiphospholipid syndrome; CHF, congestive heart failure; CKD, chronic kidney disease; HCQ, hydroxychloroquine; HTN, hypertension; ITP, idiopathic thrombocytopenic purpura; IV, intravenous; IVIG, intravenous immunoglobulin; K/C, known case; LMWH, low molecular weight heparin; SLE, systemic lupus erythematosus; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TTP, thrombotic thrombocytopenic purpura; Y/O, year-old.

Overall, the time of onset of the hematologic autoimmune presentations from the SARS-CoV-2 infection presentations and not from the time of COVID-19 diagnosis is demonstrated in Table 1. The mean time for all categories of hematologic autoimmune disorders was 11.8 ± 7.1 days (95% confidence interval of 10.4–13.3); the mean time in ITP, AIHA, APLS, TTP and Evans syndrome were 13.3 ± 7.3, 8.9 ± 5.02, 14 ± 7.5, 4.6 ± 1.5 and 5.5 ± 2.1, respectively.

Among these patients, 88 patients were alive and in the recovery process and their hematological indices related to the autoimmune disorders improved. Among the deceased cases, three were with AIHA, two were with ITP and one was afflicted to APLS. All three patients with AIHA deceased early, two due to the hemodynamic collapse as a result of the hemolysis process and one due to delayed detection of intracerebral hemorrhage. Among the two deceased patients with ITP, one died of an intracerebral hemorrhage within first 24 h and the other responded significantly to the treatment but passed away due to his poor condition and not due to the autoimmune sequel. For the deceased patient with APLS, the medical team decided to discontinue the plasmapheresis due to their concern of possible removal of antibodies needed for the adaptive response to infection. There were no statistically significant association between the presence of age, gender, having comorbidity and timing of hematological presentation and outcome (recovered or deceased) of the study cases (all p-values were above .05). Therefore, it could be concluded that among those who the autoimmune disorder-oriented treatment was administered (93 out of 94 patients), the remission rate was 95.6% (89 out of 93 patients).

Among the patients with ITP, 15 patients received intravenous immunoglobulin (IVIG), 13 patients received steroids, 13 patients received a combination of IVIG and steroid, 6 patients received a combination of IVIG and thrombopoietin-receptor agonist (TPO-RA) and 4 patients received only supportive care including platelet cell transfusion and treatment of the underlying disorder which is the SARS-CoV-2 infection. Among the patients who started their treatment with IVIG, two patients failed to respond to IVIG (86% remission rate) and further steroid was added to their treatment regimen and then their platelet level was raised. Similarly, among those with steroid, response was not observed in two patients (84% remission rate) and IVIG was initiated for them. The majority of patients who developed AIHA were treated with supportive care (59%) and for others steroid or combination of steroid with IVIG or immunosuppressor medications was administered.

Discussion

Through our study, it was revealed that AIHA, ITP, TTP, APS, autoimmune neutropenia and Evans syndrome are among the observed hematologic autoimmune sequels in the patients infected with SARS-CoV-2 infection. However, the exact pathogenesis from which these autoimmune sequels are developing remains to be fully determined. Although one could label these autoimmune disorders as incidental findings in the patients with SARS-CoV-2 infection, there are a number of evidences that are in favor of the existence of a causative relationship. From a pathogenesis point of view, secondary to viral infection, immunological tolerance could be disturbed through a variety of mechanisms that include molecular mimicry, bystander activation, epitope spreading and autoreactive effector cells immortalization [8]. Several viral infections have been identified so far to be associated with hematologic autoimmune disorders such as human immunodeficiency virus, hepatitis C virus and Epstein–Barr virus [68]. Therefore, CoV infection could be attributed to trigger a cascade of both the innate and adaptive immune arms activation resulting in autoimmunity. Consistently, previous studies on other coronaviruses, SARS-CoV-2’s cousins with a high rate of similarity in their genomic sequence and receptor-binding domains, revealed that this viral family could also lead to autoimmune disorders including hematologic ones [69–71]. Furthermore, the temporal sequence of autoimmune events described in Table 1 suggests that COVID-19 could play a causal role.

The mean days between the presentations of the hematologic autoimmune disorders and the presentations of SARS-CoV-2 infection were 11.8 ± 7.1 days for the included cases. Consideration of this point could help in early susception of an autoimmune underlying basis in the case of deterioration of the clinical condition or when there is an abnormal hematologic index even in the COVID-19 setting (for example, in these patients, thrombocytopenia is frequently seen but very low level of platelet which led to bleeding diathesis or bleeding complications is rare [72]), especially when the event occurs in 10–13 days after the first manifestations of the infection.

A wide range of hematologic abnormalities have been observed in the patient with SARS-CoV-2 infection [73]. Among these hematologic abnormalities, a hypercoagulable state associated with thromboembolic complications and poor prognosis develops in a majority of patients [74]. However, in about one-third of patients with SARS-CoV-2 infection, mild to severe degree of thrombocytopenia is found [75]. Several possible mechanisms for thrombocytopenia in the course of CoV infection have been proposed including platelet production insufficiency rooted from classic cytokine storm in infectious diseases or direct attack on hematopoietic stem cells, increased peripheral platelet destruction and declined circulating platelet secondary to lung injury [76–78].

In most patients experiencing thrombocytopenia in the course of infection, there are no definitive data revealing increased risk of bleeding and the platelet count did not decrease to a level at which bleeding occurs [76]. A small subgroup of this thrombocytopenia is found to be immune-mediated in which the immune response had been triggered by SARS-CoV-2 infection [79]. An immune etiology should be specially considered in the setting of acute and profound decrease in the platelet count in which no other causes are found, especially those that may induce abrupt feature of thrombocytopenia. Consistently, in the ITP cases reported in Supplementary material 1, first, a series of paraclinical workups, such as viral markers, peripheral blood smear and/or bone marrow study, were done for patients with abnormally low platelet count to excluded classic causes of thrombocytopenia and then, the diagnosis of ITP was made in the case with the absence of any demonstrable primary disease [80]. For example, as a noticeable percent of patients with COVID-19 are indicated to receive anticoagulation, heparin-induced thrombocytopenia should always be kept in mind. It is important to take the patients’ setting into the consideration of diagnosis; in pregnant women, HELLP syndrome (Hemolysis, Elevated Liver function tests, Low Platelet count) and gestational thrombocytopenia should be suspected and evaluated. Furthermore, meticulously and detailed history for potential risk factors for the emergence of ITP could help in diagnosis. A majority of cases reported to have ITP, had a risk factor including a previous ITP episode, use of immunomodulating medications, chemotherapy, etc.

Given the multiorgan involvement and multifaceted nature of SARS-CoV-2 infection and the complexity of its management, development of newly diagnosed or recurrent ITP may raise many therapeutic challenges. Besides inherent hypercoagulable state seen in most cases with COVID-19, ITP, itself and its treatment-related factors such as thrombopoietin-receptor agonists are also reported to be associated with a mild elevation in thrombotic risk [77]. Management of these coexisting conditions warrants an individualized approach to achieve a precise balance between the risk of severe bleeding and of thromboembolic events. Furthermore, there is still lack of data whether the available treatment options could interfere with the adaptive immune response against the pathogen that has already assaulted the body.

The treatment regimens for ITP target mainly whether the immune-mediated peripheral platelet destruction process or the thrombopoiesis process occurred in the bone marrow. Routinely, in most patients with ITP, the first-line treatment consists of IVIG or steroid or a combination of both [81]. Likewise, in the study cases described in Table 1, most cases received the first-line therapy and their platelet level increased in response to the treatment. About 90% of patients for whom first-line therapy was administrated (40 out of 44 patients), the response was observed. Steroid treatment is the most widely used standard first-line therapy for the management of new-onset or relapsed ITP. Although steroid administration theoretically poses a higher risk of the development of viral infection and may lead to suppression of immune system [82], in the cases with ITP who received steroid, no worsening of COVID-19 course or symptoms were reported. However, further evidence with more robust methodology and design is required to fill the gap. Another concern associated with glucocorticoid use is that as seen in Table 1, most patients with ITP had an underlying disease which warranted great caution for the use of glucocorticoids including hypertension, hyperglycemia and osteoporosis, etc [83]. In these cases, it should be considered to use the minimum necessary dose and duration. Another first-line therapy for ITP is IVIG, which is more suggested for cases with very low levels of platelet and at risk for severe bleeding; many patients respond to IVIG within the first 24 h of its administration and typically the increase is observed in the platelet count in 2–4 days in those who are going to respond to IVIG while the improvement of platelet count in the course of glucocorticoids takes several days to weeks [84]. Although, first-line treatment failure was not common in the reported cases of COVID-19 with ITP (six patients who later responded to the second therapeutic regimens), it should be considered to strictly monitor the hematological indices to avoid foreseeable complications. A practical guideline by Pavord et al. [77] for the management of ITP recommends to use steroids as the first-line option with minimum dosing and duration and suggest to use IVIG in two settings: as a first-line option in those with risk for severe bleeding and as an alternative in those who failed to respond to steroids.

Studies have shown that there is a high risk of coagulopathy and thrombosis formation in patients with COVID -19 [74,85]. Although the exact mechanisms involved remain unclear, it could be assumed that expression of procoagulant and antifibrinolytic factors is attributed mostly to systemic inflammatory state, endothelial activation and hypoxia resulting in altered hemostatic balance [74]. However, an additional factor is detected in bloodstream circulation of patients with SARS-CoV-2 infection with a higher rate of activation of blood coagulation and thrombosis. This additional factor is the presence of antiphospholipid antibodies indicating an APS-like condition including lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein antibodies. In a study on 150 patients with COVID-19 hospitalized in the intensive care unit, 64 thrombotic events were observed that most of the patients with these events had positive antiphospholipid antibodies [85]. Zhang et al. [62] described three critically ill patients diagnosed with COVID-19 who developed thromboembolic events. These patients were detected to be positive for Anticardiolipin and anti-β2-glycoprotein antibodies which is indicative of a notion of APS-like phenotype in these patients.

Another hematologic autoimmune disorder seen in patients with COVID-19 is AIHA. This disorder should mainly be suspected in patients with severe anemia and those with an abrupt decrease in their hemoglobin concentration in the setting that no other attributable cause be identified. As the mainstay of treatment for AIHA, especially cold agglutinin syndrome, is the detection of the underlying cause and its specific treatment, it is important to diagnose SARS-CoV-2 infection in the asymptomatic patients and those with mild symptoms. These findings may suggest to gather samples for SARS-CoV-2 RT–PCR in all new-onset hemolytic anemia even with minor or without respiratory symptoms. In most patients with AIHA of this systematic review, the hemoglobulin level stabilized in response to supportive therapy including packed cell transfusion and the use of steroid or immunomodulators should be preserved for those with treatment failure and those warrant a rapid correction of hemodynamic status [86].

Conclusion

Even with confirmation of the diagnosis of hematologic autoimmune disorder in the patients, a causative relationship between SARS-CoV-2 infection and these autoimmune events still requires further studies. These systematic reviews help us gain a more comprehensive understanding of the risk of development of hematologic autoimmune disorders in infected patients; besides, it helps us always consider an autoimmune etiology for cases with abnormal hematologic finding which further led to an appropriate treatment of the patients, especially when the symptoms present in about 1–2 weeks after the first manifestation of the infection symptoms. With this in mind, the doctor will constantly monitor the patient and consider the likelihood of such events occurring. This will result in the prompt physician’s clinical suspicion when the early manifestations of the autoimmune disorders of the patient appear. Maybe, at least in this SARS-CoV-2 pandemic, it should be recommended to evaluate patients with an unexpected and unexplained decrease in their hemoglobulin or platelet count for SARS-CoV-2 infection. Another challenging issue in this field is treatment regimens for ITP. Based on the literature, it is suggested that, in overall, steroids be used as the first line of therapy if there are no contraindications; however, given the multiorgan involvement and multifaceted nature of SARS-CoV-2 infection, an individualized approach should be taken for each patient.

Disclosure statement

No potential conflict of interest was reported by the author(s).