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Antirheumatic drugs, B cell depletion and critical COVID-19: correspondence on ‘Clinical course of coronavirus disease 2019 (COVID-19) in a series of 17 patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine’ by Mathian et al
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  1. Quirin Notz1,
  2. Patrick Meybohm1,
  3. Peter Kranke1,
  4. Dirk Weismann2,
  5. Christopher Lotz1,
  6. Marc Schmalzing3
  1. 1Department of Anesthesiology and Critical Care, Universitätsklinikum Würzburg, Würzburg, Germany
  2. 2Department of Internal Medicine I, Critical Care, Universitätsklinikum Würzburg, Würzburg, Germany
  3. 3Department of Internal Medicine II, Rheumatology, Universitätsklinikum Würzburg, Würzburg, Germany
  1. Correspondence to Dr Quirin Notz, Department of Anesthesiology and Critical Care, Universitätsklinikum Würzburg, Würzburg 97080, Germany; Notz_Q{at}ukw.de

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In a recent case series, Mathian et al reported on 17 patients suffering from systemic lupus erythematosus and COVID-19.1 All of these patients received long-term hydroxychloroquine treatment and initial signs and symptoms of COVID-19 were similar to those previously described. However, as 50% of the patients remained hospitalised at the time of publication, the authors cannot comment on the duration and eventual outcome of COVID-19 in all of their patients. Furthermore, it is emerging that hydroxychloroquine does not alter COVID-19.2–4 As such, we actually believe that other immunosuppressive, antirheumatic medications require more attention. Mathian et al rightfully pointed out that besides long-term hydroxychloroquine treatment, steroids and other baseline immunosuppressant drugs are often present in patients with rheumatic diseases. In this context, we found an altered immune response and noticeable prolongation of COVID-19 from the onset of symptoms to intensive care unit (ICU) admission in two patients pretreated with rituximab (RTX) (table 1).

Table 1

Clinical course

Patient A (aged 40–60 years) suffered from rheumatoid arthritis, treated with daily doses of leflunomide and low-dose prednisolone. RTX was administered every 6 months. The patient was admitted to ICU 33 days after the onset of COVID-19 symptoms with severe acute respiratory distress syndrome and massively elevated interleukin-(IL-) 6 levels. A good response to low-dose circulatory support with norepinephrine and prone positioning improved the clinical situation. Extubation was successful on day 41 and the patient could be discharged from the ICU on day 44 in stable condition. Patient B (aged 40–60 years) presented himself to a regional hospital 19 days after the onset of fever and dyspnoea. COVID-19 was diagnosed and mechanical ventilation became necessary. Four months prior, the patient received an autologous haematopoietic stem cell transplantation due to a mantle cell lymphoma. Chemotherapy among others included RTX. Despite ARDS treatment and the use of IL-1 receptor antagonist anakinra to treat macrophage-activation-like syndrome, the clinical condition worsened. Transfer to tertiary care ICU was necessary on day 34. Massively elevated IL-6 and ferritin levels indicated hyperinflammation and treatment with tocilizumab was initiated. Moreover, the patient received hydrocortisone, convalescent plasma, granulocyte colony stimulating factor and immunoglobulins. After a complex clinical course, including acute renal failure, massive bilateral pulmonary embolism, episodes of ventricular tachycardia and a subarachnoid haemorrhage, the patient was successfully weaned from mechanical ventilation and finally discharged from ICU on day 58 without major respiratory or neurological residues.

Both patients had severe lymphocytopenia on ICU admission and B cell depletion persisted throughout the course of treatment, as repeatedly confirmed via flow cytometry. The patients were neither able to establish any anti-SARS-CoV-2-spike-receptor binding domaine (RBD) antibody titres, nor to eliminate the virus, as pharyngeal swabs and tracheal aspirates tested positive for SARS-CoV-2 until ICU discharge (figure 1).

Figure 1

The prolonged clinical courses of the two patients are shown. Day 0 represents the admission on tertiary care intensive care unit (ICU). The onset of COVID-19 is marked with light red and blue bars; hospitalisation in a secondary care centre is highlighted in blue and red bars. The clinical course on ICU is represented by sequential organ failure assessment score with a line in corresponding colours. The line stops at the time of discharge from ICU. Patients had a continuous B cell depletion after rituximab treatment, as repeatedly confirmed via flow cytometry (representative inlays in corresponding colours, CD19 positivity indicated B cells). RNA from SARS-CoV-2 was positive (+) during the whole ICU stay. Anti-SARS-CoV-2-spike-receptor binding domaine (RBD) antibodies were negative (−) at all time.

Previously a prolonged course of COVID-195 was attributed to the lack of B cell antigen presentation, which might concomitantly impair activation of immune cells and cytokine production.6 We rather observed excessive immune activation and cytokine release with high proinflammatory markers. Hyperinflammation in the absence of B cells underlines the predominant role of the myeloid and T cell system in COVID-19 cytokine storm. The second interesting finding was that both patients could probably not completely clear the virus. This highlights the role of the B cell system and antibody production for virus elimination, as potentially neutralising anti-SARS-CoV-2-Spike-RBD antibodies were not detectable in both RTX patients. Nonetheless, the clinical situation improved, indicating that deterioration was rather driven by the immune system and not by sheer presence of virus.

Overall, the case series by Mathian et al and our observations indicate that the presence of complex antirheumatic drug regimens further complicates COVID-19. However, the question if these patients are at risk of a more severe or just delayed course of COVID-19 remains unanswered. Larger and adequately powered studies are required, which concomitantly would provide evidence on how to handle immunosuppression in times of COVID-19.

Compliance with ethical standards

The institutional ethic board of the University of Wuerzburg waived the need for a specific approval due to the context of sole retrospective chart review within standard care (63/20-kr 25.03.2020). Both patients have consented to the submission of this article to the journal. On behalf of all authors, the corresponding author states that there is no conflict of interest relating to the current work.

References

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Footnotes

  • Contributors QN, CL and MS conceptualised the work, collected the data, wrote and revised the manuscript. QN has prepared the figure. PM, PK and DW revised the manuscript and provided resources.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Obtained.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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