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• Response to Dr. Yudong Liu
  Marvin J. Fritzler, Uriel Trahtemberg
  Published on: 4 November 2021
• The autoimmune feature of severe COVID-19
  Yudong Liu
  Published on: 20 October 2021
• Rujittika Mungmunpuntipantip and Viroj Wiwanitkit Response
  Marvin J Fritzler
  Published on: 25 August 2021
• COVID-19, autoantibody and clinical outcome
  rujittika mungmunpuntipantip, viroj wiwanitkit
  Published on: 20 August 2021

• Published on: 4 November 2021

  Response to Dr. Yudong Liu

  • Marvin J. Fritzler, Professor of Medicine University of Calgary, Cumming School of Medicine
  • Other Contributors:
    • Uriel Trahtemberg, Critical Care Physician and Affiliate Scientist

  We thank Dr. Yudong Liu for commenting on our manuscript and on many of the same issues we raised 1. There are, however, some comments that require clarification and a response. It is true that anti-phospholipid antibodies (APLA) of various specificities and immunoglobulin isotypes have been reported in COVID-19 2. However, despite a historical connection of APLA with coagulopathies and anti-phospholipid syndrome (APS), to date there is no convincing evidence that APLA have this in vivo pathogenic effect in COVID-19. In our patients, despite the presence of APLA (e.g., IgG anti-cardiolipin), there was no link to thrombotic events, a finding echoed by other referenced studies 3 and recently reviewed 2,4. The recent publication by Chang et al 5 is mentioned but it is important to appreciate that their results were compared to “normal” controls and no clinical features (coagulopathy or APS) were reported, precluding any inferences to autoimmune diseases; it is a standalone description of COVID-19 findings. Like the Chang manuscript, we also reported an extensive array of autoantibodies in COVID-19, but when we used sera from contemporaneous non-COVID patients of similar disease severity as comparator controls, we did not find significant differences in the autoantibody repertoire between the COVID positive and negative cohorts 6. Many individuals displayed “certain autoimmune features” but that cannot be taken to be equivalent to autoimmune disease. Indeed, COVID-19 patients...

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  We thank Dr. Yudong Liu for commenting on our manuscript and on many of the same issues we raised 1. There are, however, some comments that require clarification and a response. It is true that anti-phospholipid antibodies (APLA) of various specificities and immunoglobulin isotypes have been reported in COVID-19 2. However, despite a historical connection of APLA with coagulopathies and anti-phospholipid syndrome (APS), to date there is no convincing evidence that APLA have this in vivo pathogenic effect in COVID-19. In our patients, despite the presence of APLA (e.g., IgG anti-cardiolipin), there was no link to thrombotic events, a finding echoed by other referenced studies 3 and recently reviewed 2,4. The recent publication by Chang et al 5 is mentioned but it is important to appreciate that their results were compared to “normal” controls and no clinical features (coagulopathy or APS) were reported, precluding any inferences to autoimmune diseases; it is a standalone description of COVID-19 findings. Like the Chang manuscript, we also reported an extensive array of autoantibodies in COVID-19, but when we used sera from contemporaneous non-COVID patients of similar disease severity as comparator controls, we did not find significant differences in the autoantibody repertoire between the COVID positive and negative cohorts 6. Many individuals displayed “certain autoimmune features” but that cannot be taken to be equivalent to autoimmune disease. Indeed, COVID-19 patients have developed Guillain Barré (not a COVID-specific condition) and there are anecdotal reports of other autoimmune diseases, but it is very important to realize that temporarily is not the same as causality 2.
  Last, it is opined that our study “failed to detect aβ2-GP1 in patients with COVID-19, but other studies reported the existence of these aPLs”. However, this comment does not seem to appreciate that we used an assay that detected antibodies to domain 1 of β2-glycoprotein1 (β2-GP1) which is known to have higher specificity for and more clearly linked to the pathogenesis of APS than antibodies to other β2-GP1 domains 7. As we clarified in our manuscript, these findings are consistent with those of with Borghi et al 3 who detected antibodies to 2GP1 domains 2 and 4 but found no association with thrombotic events in COVID19 in 122 severe COVID-19 patients, once again challenging the notion that anti-2GP1 has any pathogenic role in COVID-19 2.

  As to the dynamic and temporal/chronological sequence of autoantibody and APLA appearance, we clearly stated that “clinical data and serum samples were collected longitudinally at days 0, 1, 3, 5, 7 and 10; after day 10 or ICU discharge.” Our data (Table 2) and discussion on APLA 1 and other autoantibodies 6 showed that in some patients autoantibodies were present on admission to intensive care (IC) while in others they appeared during the stay in IC and in some the autoantibodies fell to within normal/reference range while in IC. Hence, the chronological autoantibody responses are quite heterogenous. We concur that important studies are still required, especially the assessment of whether autoimmunity evolves to autoimmune diseases in COVID-19 or following vaccination, as well as in long -COVID and multi-inflammatory syndrome.

  References

  1 Trahtemberg U, Rottapel R, Dos Santos CC, Slutsky AS, Baker A, Fritzler MJ. Anticardiolipin and other antiphospholipid antibodies in critically ill COVID-19 positive and negative patients. Ann Rheum Dis 2021; 80 (9):1236-1240. doi: 10.1136/annrheumdis-2021-220206.
  2 Meroni PL, Borghi MO. Antiphospholipid antibodies and COVID-19 thrombotic vasculopathy: one swallow does not make a summer. Ann Rheum Dis 2021; 80(9):1105-1107. doi: 10.1136/annrheumdis-2021-220520.
  3 Borghi MO, Beltagy A, Garrafa E, Curreli D, Cecchini G, Bodio C et al. Anti-Phospholipid Antibodies in COVID-19 Are Different From Those Detectable in the Anti-Phospholipid Syndrome. Front Immunol 2020; 11:584241-doi: 10.3389/fimmu.2020.584241.
  4 Knight JS, Caricchio R, Casanova JL, Combes AJ, Diamond B, Fox SE et al. The intersection of COVID-19 and autoimmunity. J Clin Invest 2021; Oct 28. Online ahead of print:e154886-doi: 10.1172/JCI154886.
  5 Chang SE, Feng A, Meng W, Apostolidis SA, Mack E, Artandi M et al. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nat Commun 2021; 12:5417-25509. doi: 10.1038/s41467-021-25509-3.
  6 Trahtemberg U, Fritzler MJ, On behalf of the COVID-19 chapter of the "Longitudinal Biomarkers in Lung Injury" study groupCollaborators. COVID-19-associated autoimmunity as a feature of acute respiratory failure. Intensive Care Med 2021; 47(7):801-804. doi: 10.1007/s00134-021-06408-z.
  7 Chighizola CB, Pregnolato F, Andreoli L, Bodio C, Cesana L, Comerio C et al. Beyond thrombosis: Anti-beta2GPI domain 1 antibodies identify late pregnancy morbidity in anti-phospholipid syndrome. J Autoimmun 2018; 90:76-83.

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  Conflict of Interest:
  None declared.

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• Published on: 20 October 2021

  The autoimmune feature of severe COVID-19

  • Yudong Liu, MD The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital

  Dear Editor,

  I read with great interest the article by Trahtemberg et al.[1] on the clinical relevance of antiphospholipid antibodies (aPLs), in particular anticardiolipin antibodies (aCLs), in critically-ill COVID-19 positive and negative patients. Severe COVID-19 is associated with a hypercoagulable state. Early studies identified the presence of aPLs in critically-ill COVID-19 patients[2], which has attracted considerable attention as the presence of aPLs is one of the mechanisms leading to coagulopathy. Substantial efforts then tried to associate the thrombotic events seen in COVID-19 to aPLs status. The results seem negative, but a number of different types of autoantibodies were identified [3]. Chang et al. recently reported that autoantibodies were present in approximately half of the hospitalized COVID-19 patients, but in less than 15% of healthy controls [4]. In addition to aCLs and anti-beta 2 glycoprotein 1 antibodies (aβ2-GP1), they also identified autoantibodies targeting autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes as well as targeting interferons/interleukins and other cytokines[4]. These findings suggest that COVID-19, in particular patients with severe/critical conditions, displayed certain autoimmune features.

  In the well-designed study by Trahtemberg et al., the authors expanded the cohort by including COVID-19 negative patients who were admitted to intensive care unit (ICU) with ac...

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  Dear Editor,

  I read with great interest the article by Trahtemberg et al.[1] on the clinical relevance of antiphospholipid antibodies (aPLs), in particular anticardiolipin antibodies (aCLs), in critically-ill COVID-19 positive and negative patients. Severe COVID-19 is associated with a hypercoagulable state. Early studies identified the presence of aPLs in critically-ill COVID-19 patients[2], which has attracted considerable attention as the presence of aPLs is one of the mechanisms leading to coagulopathy. Substantial efforts then tried to associate the thrombotic events seen in COVID-19 to aPLs status. The results seem negative, but a number of different types of autoantibodies were identified [3]. Chang et al. recently reported that autoantibodies were present in approximately half of the hospitalized COVID-19 patients, but in less than 15% of healthy controls [4]. In addition to aCLs and anti-beta 2 glycoprotein 1 antibodies (aβ2-GP1), they also identified autoantibodies targeting autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes as well as targeting interferons/interleukins and other cytokines[4]. These findings suggest that COVID-19, in particular patients with severe/critical conditions, displayed certain autoimmune features.

  In the well-designed study by Trahtemberg et al., the authors expanded the cohort by including COVID-19 negative patients who were admitted to intensive care unit (ICU) with acute respiratory failure. They found that aCLs were present in 59% severe COVID-19 patients, but were also detected in 35% contemporaneous non-COVID-19 patients. They also identified the presence of a broad range of non-antiphospholipid syndrome (APS) autoantibodies as well as anti-cytokine autoantibodies. Specifically, over 50% patients were positive for anti-nuclear antibodies (ANA), and 38% patients were positive for anti-cytokine autoantibodies [1]. These findings thus confirmed and extended previous observations that the autoimmune feature may be not restricted to severe COVID-19, but may be a common feature of severe respiratory diseases.

  aPLs can be induced in a number of virus infections, but ANA and other autoantibodies are normally absent [5]. However, a broad range of autoantibodies, in particular ANA, are present in severe COVID-19, rendering the severe COVID-19 more resemble of a systemic autoimmune disease. In fact, by detailed characterization of B cell responses through high-dimensional flow cytometry, Woodruff et al. have found that the immunological landscape associated with effector B cell mobilization in COVID-19 is highly similar to the one observed in patients with active autoimmune processes, and in particular with active systemic lupus erythematosus (SLE)[6]. Instead of predicting thrombotic events, the autoimmune features may be associated with disease severity. Trahtemberg et al.[1] found that the presence of aCLs was associated with more severe disease independent of COVID-19 status, which is consistent with the findings by Woodruff et al., who have found that disease severity and poor clinical outcomes of COVID-19 are closely correlated with intense activation of the extrafollicular B cell pathway that leads to the generation of autoreactive antibody-secreting cell (ASCs) responses [6]. Multiple tissues/organs damage due to widespread and overwhelming inflammation (i.e. cytokine storm) during severe COVID-19 may result in excessive generation and accumulation of autoantigens [7], which could boost production of autoantibodies that had previously existed at very low levels in the body.

  Although Trahtemberg et al.’s work provide critical insights that transient breakage of immune tolerance and the generation of autoantibodies may be a common phenomenon in severe viral infections, a number of questions need to be answered in furture studies. For example, the presence of autoantibodies in COVID-19 displayed substantial heterogeneity in terms of types and titers. For example, Trahtemberg et al. [1] failed to detect aβ2-GP1 in patients with COVID-19, but other studies reported the existence of these aPLs [2, 4, 8, 9]. Xiao et al. showed that the levels of aPLs rapidly decreased after hitting the peak [9]. It seems that the emergence of autoantibodies is due to a sporadic loss of self-tolerance. It thus remains unknown when aPLs first emerged and the chronological order of the emergence of different aPLs. It also remains unclear whether ANAs and other autoantibodies (i.e. anti-cytokine antibodies) follow the similar pattern. The timing of sample collection seems an important factor. Second, COVID-19 and some autoimmune disorders (i.e. SLE or APS) share some clinical and laboratory similarities. It has been reported that some patients develop autoimmune diseases, such as Guillain-Barre syndrome or SLE, after COVID-19 infection [10]. It is thus unclear whether or not COVID-19 infection accelerates the pathological process in these predisposed subjects, or just a coincidence. Third, it remains to be determined whether or not vaccinated subjects develop autoantibodies after being infected by SARS-CoV-2, especially in those who have severe COVID-19.

  References
  1. Trahtemberg U, Rottapel R, Dos Santos CC, Slutsky AS, Baker A, Fritzler MJ. Anticardiolipin and other antiphospholipid antibodies in critically ill COVID-19 positive and negative patients. Ann Rheum Dis. 2021 Sep; 80(9):1236-1240.
  2. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020 Apr 23; 382(17):e38.
  3. Vojdani A, Kharrazian D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin Immunol. 2020 Aug; 217:108480.
  4. Chang SE, Feng A, Meng W, Apostolidis SA, Mack E, Artandi M, et al. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nat Commun. 2021 Sep 14; 12(1):5417.
  5. Mendoza-Pinto C, Garcia-Carrasco M, Cervera R. Role of Infectious Diseases in the Antiphospholipid Syndrome (Including Its Catastrophic Variant). Curr Rheumatol Rep. 2018 Aug 20; 20(10):62.
  6. Woodruff MC, Ramonell RP, Nguyen DC, Cashman KS, Saini AS, Haddad NS, et al. Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nat Immunol. 2020 Dec; 21(12):1506-1516.
  7. Wilson JG, Simpson LJ, Ferreira AM, Rustagi A, Roque J, Asuni A, et al. Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis. JCI Insight. 2020 Sep 3; 5(17).
  8. Borghi MO, Beltagy A, Garrafa E, Curreli D, Cecchini G, Bodio C, et al. Anti-Phospholipid Antibodies in COVID-19 Are Different From Those Detectable in the Anti-Phospholipid Syndrome. Front Immunol. 2020; 11:584241.
  9. Xiao M, Zhang Y, Zhang S, Qin X, Xia P, Cao W, et al. Antiphospholipid Antibodies in Critically Ill Patients With COVID-19. Arthritis Rheumatol. 2020 Dec; 72(12):1998-2004.
  10. Liu Y, Sawalha AH, Lu Q. COVID-19 and autoimmune diseases. Curr Opin Rheumatol. 2021 Mar 1; 33(2):155-162.

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  Conflict of Interest:
  None declared.

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• Published on: 25 August 2021

  Rujittika Mungmunpuntipantip and Viroj Wiwanitkit Response

  • Marvin J Fritzler, Clinician Scientist University of Calgary

  We thank Mungmunpuntipantip and Wiwanitkit for their response and comments on our manuscript and their local experience. Of note, the serologies of the cohort we presented were tested repeatedly during the hospitalization, not only at admission. Also, for reference, the days from symptom onset to ICU admission are presented in Table 3 of the manuscript".

  Conflict of Interest:
  None declared.

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• Published on: 20 August 2021

  COVID-19, autoantibody and clinical outcome

  • rujittika mungmunpuntipantip, academic Private Academic Consultant, Bangkok Thailand
  • Other Contributors:
    • viroj wiwanitkit, medical professor

  COVID-19, autoantibody and clinical outcome
  Rujittika Mungmunpuntipantip1,Viroj Wiwanitkit2
  1.Private Academic Consultant, Bangkok Thailand
  2. Dr DY Patil University, Pune, India
  Correspondence
  Rujittika Mungmunpuntipantip
  Private Academic Consultant, Bangkok Thailand
  Email: rujittika@gmail.com

  Dear Editor, we would like to share ideas and experience on “Anticardiolipin and other antiphospholipid antibodies in critically ill COVID-19 positive and negative patients [1].” Trahtemberg et al. concluded that “Positive APLA serology was associated with more severe disease regardless of COVID-19 status [1].” In the study, the laboratory data on the day of admission are referred to. In individual patient, the period of illness before admission might be different and whether this period affects affect clinical outcome or not is an interesting question. In COVID-19, the development of COVID-19 is reported and the rate of positive autoimmunity is different in different reports [2]. In our settings, positive autoantibody is detectable after complete recovery from COVID -19 among patients with history of previously autoantibody negative. Hence, it might be difficult to interpret the clinical association of positive autoantibody at first admission.

  Conflict of interest
  None

  References
  1. Trahtemberg U, Rottapel R, Dos Santos CC, Slutsky AS, Baker A, Fritzler MJ. Anticardi...

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  COVID-19, autoantibody and clinical outcome
  Rujittika Mungmunpuntipantip1,Viroj Wiwanitkit2
  1.Private Academic Consultant, Bangkok Thailand
  2. Dr DY Patil University, Pune, India
  Correspondence
  Rujittika Mungmunpuntipantip
  Private Academic Consultant, Bangkok Thailand
  Email: rujittika@gmail.com

  Dear Editor, we would like to share ideas and experience on “Anticardiolipin and other antiphospholipid antibodies in critically ill COVID-19 positive and negative patients [1].” Trahtemberg et al. concluded that “Positive APLA serology was associated with more severe disease regardless of COVID-19 status [1].” In the study, the laboratory data on the day of admission are referred to. In individual patient, the period of illness before admission might be different and whether this period affects affect clinical outcome or not is an interesting question. In COVID-19, the development of COVID-19 is reported and the rate of positive autoimmunity is different in different reports [2]. In our settings, positive autoantibody is detectable after complete recovery from COVID -19 among patients with history of previously autoantibody negative. Hence, it might be difficult to interpret the clinical association of positive autoantibody at first admission.

  Conflict of interest
  None

  References
  1. Trahtemberg U, Rottapel R, Dos Santos CC, Slutsky AS, Baker A, Fritzler MJ. Anticardiolipin and other antiphospholipid antibodies in critically ill COVID-19 positive and negative patients. Ann Rheum Dis. 2021 Sep;80(9):1236-1240.
  2. Muratori P, Lenzi M, Muratori L, Granito A. Antinuclear antibodies in COVID 19. Clin Transl Sci. 2021 May 1:10.1111/cts.13026. doi: 10.1111/cts.13026. Online ahead of print.

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  Conflict of Interest:
  None declared.

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