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SARS-CoV-2 and Autoimmune Cytopenia
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a variety of clinical manifestations related to viral tissue damage, as well as a virally induced immune response. Hyperstimulation of the immune system can serve as a trigger for autoimmunity. Several immune-mediated manifestations have been described in the course of SARS-CoV-2 infection. This review highlights COVID associated autoimmune hemolytic anemia and immune thrombocytopenic purpuria (ITP).
Since the first case of infection with novel SARS-CoV-2 virus was reported in Wuhan China in December of 2019, over 166 million people have been diagnosed and 3.4 million have died worldwide, as of 22 May 2021, and 1.6 billion doses of SARS -CoV-2 vaccines have been distributed . This pandemic has had a devastating impact on human lives and has brought immense burden to the healthcare system. Symptoms of the infection range from asymptomatic infection, in at least 30% of cases , and mild respiratory illness, to severe complications, such as acute respiratory distress syndrome (ARDS) and multi-organ failure .
Activation of the immune system induced by SARS -CoV-2 can also contribute to the disease pathogenesis and organ damage. Immune hyperstimulation and dysregulation can lead to marked cytokine release syndrome, macrophage activation, and systemic hyperinflammation. Supporting the role of the inflammation-induced tissue damage, immunomodulatory and immunosuppressive agents have shown to have efficacy in the treatment of coronavirus disease 2019 (COVID-19), particularly in severe cases .
Hyperactivation of the immune system can trigger autoimmune manifestations in patients with prior history of autoimmune disease, as well as prompt the development of de novo autoimmune manifestations. Infections are an established risk factor for the development of autoimmune cytopenias. Viral infections linked to autoimmune hematologic disorders include the human immunodeficiency virus, hepatitis C virus and cytomegalovirus, parvovirus B19, Epstein–Barr virus, and Zika virus . SARS-CoV-2 infection has been associated with several autoimmune complications, including cutaneous rashes and vasculitis, autoimmune cytopenia, anti-phospholipid syndrome, central and peripheral neuropathy, myositis, and myocarditis . In a systematic review of 94 patients with COVID-19 who developed hematologic autoimmune disorders in their course of infection, the most common hematologic autoimmune disorder was immune thrombocytopenic purpura (ITP), seen in 58%, followed by autoimmune hemolytic anemia (AIHA) in 23% .
2. COVID-19 and Activation of the Immune System
Cytokine storm syndromes, such as ARDS and hemophagocytic lymphohistiocytosis (HLH), are seen in a subgroup of severely ill patients with COVID-19, supporting the role of the immune system dysregulation in the SARS-CoV-2 infection . Both mild and severe forms of COVID-19 disease have been associated with changes in circulating leukocyte subsets and the upregulation of cytokine secretion, where marked increases in the secretion of cytokines of IL-6, IL-1β, IL-10, IL-17, TNF, and GM-CSF, referred to as ‘cytokine storm’, are seen in severe cases . In addition, an imbalance in the Th17/Treg ratio and lower levels of regulatory T cells, which are involved in the downregulation of the immune response, have also been described in severe cases . Mobilization of Th17 responses has been implicated in the pathogenesis of autoimmune diseases, including autoimmune hemolytic anemia , and low levels of regulatory CD4 T cells have been seen in patients with warm AIHA and ITP . Lower levels of regulatory T cells in COVID-19 patients with severe infections can explain the higher rate of ITP in severe cases .
Multiple autoantibodies have been reported in association with SARS-CoV-2 infection, including antinuclear antibodies, cytoplasmic anti-neutrophil cytoplasmic antibodies, perinuclear anti-neutrophil cytoplasmic antibodies, anti-actin antibodies, and anti-mitochondrial antibodies . High rates of lupus anticoagulant positivity rates associated with thrombosis, as well as anticardiolipin (aCL) and beta2 glycoprotein I (β2GPI), were reported in patients with COVID-19 infection . Anti-heparin/platelet factor 4 (PF4) antibodies, which are associated with platelet activation in heparin-induced thrombocytopenia (HIT), have been recognized in severely ill COVID-19 patients with a HIT syndrome . Some cases of HIT and positive PF4 antibodies have been reported without prior heparin exposure . Antibodies to ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, with a clinical syndrome of thrombotic thrombocytopenic purpura (TTP), were described as well .
Cross-reactivity between SARS-CoV-2 proteins and a variety of tissue antigens has been reported , supporting the role of molecular mimicry in the development of autoantibodies . A structural similarity between ankyrin 1, a red blood cell membrane adaptor protein defective in patients with hereditary spherocytosis, and the SARS-CoV-2 surface glycoprotein, named the “spike protein”, has been demonstrated . A positive direct antiglobulin (DAT) test, which detects the presence of antibodies and or complement on the surface of red blood cells, has been reported in 13% of 267 anemic COVID-19 patients in one study, with higher rates of positivity in the ICU patients . Another study reported a positive DAT in 46% of the 113 patients with COVID-19 .
In addition, greater than one-third of the immunogenic proteins in SARS-CoV-2 have been shown to have homology to proteins essential in the human adaptive immune system, providing support to the role of pathogenic priming in disease severity by induction of autoimmunity . Induction of the autoimmune response against proteins in the adaptive immune system can impair major histocompatibility complex (MHC) class I and class II antigen presentation, cross-presentation of exogenous antigens, and programmed cell death protein 1 (PD-1) signaling , further contributing to immune dysregulation.
3. SARS-CoV-2 Infection in Patients with History of Autoimmune Disease
Patients with a history of autoimmune disease are potentially at risk for SARS-CoV-2 infection due to underlying immune dysregulation and use of immunosuppressive therapies. Alternatively, many immunomodulatory agents used in autoimmune diseases are utilized in the therapy of severe SARS-CoV-2 infection and can potentially curb the immune response and associated organ damage. It appears that SARS-CoV-2 infection in patients with autoimmune diseases runs a generally mild course, comparable to that of the general population. A cross-sectional study of 916 patients with autoimmune rheumatologic disorders in Italy identified 148 symptomatic patients. Symptoms were typically mild and similar to the general population and no deaths were seen . A case registry of 600 patients from 40 countries from the Global Rheumatology Alliance reported a more severe course, with 46% patients requiring hospitalization and 9% resulting in death . In a prospective case series of 86 patients with a history of immune-mediated inflammatory diseases treated with anticytokine biologics and/or other immunomodulatory therapies who developed confirmed or highly suspected symptomatic SARS-CoV-2 infection, the incidence of hospitalization was 16%, with one case of mortality among 14 admitted patients. This was comparable to the incidence of hospitalization in the general population .
With regards to SARS-CoV-2 infection in autoimmune cytopenias, in a cohort of 501 patients in northern Italy with autoimmune cytopenias, which included 139 patients with warm AIHA (wAIHA), 108 patients with cold agglutinin disease (CAD), and 103 patients with ITP, four patients developed SARS-CoV-2 pneumonia. Among those, three patients had autoimmune hemolytic anemia (one CAD, one wAIHA, and one Evan’s syndrome) and one had ITP. Relapse of hemolysis was seen in one patient with CAD and one with Evan’s syndrome, and was successfully treated with transfusion and steroids . An unfortunate case of recurrent warm autoimmune hemolytic anemia in the setting of COVID-19 infection complicated by lethal cryptococcal sepsis and encephalitis in the setting of immunosuppression with cyclophosphamide and steroids has been reported as well .
In the largest series of 32 chronic ITP patients who tested positive for SARS-CoV-2 a median of 39 months after ITP diagnosis, 56% of patients had moderate to severe COVID-19 disease requiring hospitalization and 38% of patients required non-invasive or invasive ventilation . However, the authors note that cases of mild or asymptomatic SARS-CoV-2 infection may have been missed given that many patients during this time were followed via telemedicine and patients were only tested if they sought medical care for COVID-19 symptoms. A total of 47% of patients had a relapse of ITP requiring treatment an average of 9 days after SARS-CoV-2 diagnosis. The patients who required hospitalization had higher rates of ITP relapse than the patients who did not require hospitalization (74% vs. 15%, p = 0.006), suggesting that relapse is more common in patients with more severe COVID-19 symptoms. Most patients who required treatment received corticosteroids, and the two patients who did not respond to corticosteroids and intravenous immunoglobulin (IVIG) expired from respiratory failure from COVID-19 disease. Given that almost half of the patients who had SARS-CoV-2 experienced a relapse of ITP, clinicians should carefully monitor patients with a history of ITP who test positive for SARS-CoV-2 for bleeding symptoms. The mortality rate in this study was 9%, and death was related to SARS-CoV-2 severity rather than bleeding associated with ITP.
Interestingly, another smaller case series of eight patients with chronic ITP who had SARS-CoV-2 showed that four (50%) of the patients presented with early thrombocytosis and three patients required antiplatelet therapy, ITP treatment discontinuation, or ITP treatment reduction . The authors speculate that lymphopenia could be responsible for the thrombocytosis, given that ITP is caused by auto-reactive B cells and altered regulatory T lymphocytes. Two patients (25%) had relapsed ITP and these patients showed a rapid response to treatment. Larger case series of patients with chronic ITP and subsequent SARS-CoV-2 infection are needed in order to clarify the association of thrombocytosis with SARS-CoV-2 infection.
4. SARS-CoV-2 as a Trigger for Development of Autoimmune Cytopenia
Table 1 summarizes reports of 15 patients who developed with cold agglutinin syndrome (CAS) in the setting of SARS-CoV-2 infection. The majority (nine) were males, and in five patients CAS was present at diagnosis. Hemolysis developed 5–20 days after the presentation in the rest of the patients. Four patients deceased as a consequence of SARS-CoV-2 infection and complications. In all other cases with available information, hemolysis resolved and patients recovered. Rituximab therapy  and plasma exchange were successfully used in one case each .
|Comorbidity||Symptoms to AIHA Development, Days||AIHA
|62 Male||HTN, oropharyngeal squamous cell carcinoma on chemoradiation||16||Transfusion||Resolved||recovered||Capes |
|breast DCIS post-mastectomy on chemoradiation||0||Transfusion
|48 Male||HTN, DM1, obesity ESRD on peritoneal dialysis||7||None||Unknown||Deceased
concurrent DVT, stroke
|ITP, asthma, splenectomy||0||Transfusion||Unknown||Deceased||Zagorski |
|80 Female||Stage A CLL||12||None||Resolved||recovered||Nesr |
|45 Male||Unknown||0||Transfusion||Unknown||Unknown||Raghuwanshi |
|77 Male||COPD, G6PD deficiency||0||Steroids||Unknown||Deceased||Gupta |
|61 Male||DM2, hypercholesterolemia, ESRD, CAD, atrial fibrillation||5||Steroids||Minimal hemolysis; Resolved||Recovered||Kaur |
|69 Female||Stage IV CLL on tirabrutinib, discontiniued||18||Steroids, Rituximab
concurrent ITP, myositis
Immune thrombocytopenic purpura (ITP) has been described in numerous case reports and case series in association with SARS-CoV-2. The incidence of ITP in SARS-CoV-2 has been described in one study as 0.34% .
The majority of new cases of ITP in SARS-CoV-2 patients have been reported in patients 50–70 years old , although cases in children as young as 1 year and up to age 95 have been reported . There have been two reported cases of pregnant women who developed de novo ITP associated with SARS -CoV-2 . The increase in prevalence in older age is similar to ITP not associated with SARS -CoV-2 . Unlike traditional ITP, SARS-CoV-2-associated ITP does not appear to be more common in younger females than in younger males, although the limited number of cases reported in patients younger than 50 might mask this association .
However, ITP can occur in patients with mild symptoms, and in one study, 7% of ITP cases were in patients with asymptomatic COVID-19 . This underscores the importance of ruling out SARS-CoV-2 in new ITP cases even if there are no COVID-19 symptoms. As the pandemic continues, patients with newly diagnosed ITP should be tested for SARS -CoV-2 in addition to other classic viral triggers.
5. Current Insights
The entry is from 10.3390/hemato2030029
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