Dear Sirs,
Individuals with autoimmune diseases, such as multiple sclerosis (MS) or neuromyelitis
optica spectrum disorder (NMOSD), that require long-term immunosuppression are regarded
as particularly vulnerable in the current COVID-19 pandemic [1]. However, few details
about the effect of individual immunotherapies have been reported, which could instruct
us about the immunological control of severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2). Specific antibodies are detectable within 2–19 days [2] and have been
extensively analyzed for diagnostic purposes [3] and vaccine development [4]. It is
unclear whether a durable antibody response is required for recovery of COVID-19 or
whether it might even contribute to the pathogenesis by perpetuating hyperinflammation
as has been shown for the closely related middle-east-respiratory-syndrome (MERS)
coronavirus [5].
Here, we report on two individuals with underlying neuroimmunological diseases who
were under stable rituximab therapy—a B cell-depleting monoclonal antibody [6, 7]—when
confirmed COVID-19 developed. Infection with SARS-CoV-2 was verified in both cases
by PCR.
Patient 1 was a 44-year-old woman with a history of breast carcinoma, which was treated
by breast-conserving surgery in 2010 and a relapsing–remitting MS (diagnosed 1999;
EDSS 2.0) that has been treated with rituximab since 2013 (last infusion in January
2020). She was admitted with malaise, muscle ache, cough, fever and mild dyspnea,
which first developed during a ski-trip in a high-risk area on March 14th, 2020 and
she was tested positive ten days later. On the day of admission, she showed elevated
inflammatory biomarkers (CRP 34 mg/L, interleukin-6 371.9 ng/L, ferritin 292.7 µg/L),
cardiac biomarkers (proBNP 253 ng/L) and D-dimers (0.61 mg/L) but normal procalcitonin
(< 0.02 µg/L) and negative blood cultures. Radiologic findings of bilateral infiltrations
indicated atypical pneumonia. On the second day of admission SARS-CoV-2 RNA was only
detectable in pharyngeal swabs in low concentrations close to detection limit (Ct
37.4). Immunologically, she had normal lymphocyte counts (1.12 billion/mL) but absent
B cells (not detectable, Supplementary Table 1). Serologically, we could not detect
antibodies against SARS-CoV-2 IgG. The patient was clinically and serologically stable
and was discharged after four days of inpatient symptomatic treatment against fever
into home quarantine. Four weeks later, she electively visited our outpatient clinic
and her PCR from a nasopharyngeal swab was now negative for SARS-CoV-2 RNA. Clinically,
she was completely asymptomatic, and we did not observe neurological deterioration.
Serologically, she was still negative for antibodies against SARS-CoV-2 IgG (Fig. 1a).
A control X-ray of the chest showed a strong regression of pre-diagnosed bilateral
pneumonic infiltrates.
Fig. 1
Summary of disease course, B cell count, PCR and antibody (Abs) response in patient
1 (a) and 2 (b)
Patient 2 was a 68-year-old female with neuromyelitis optica spectrum disorder (NMOSD,
diagnosed 2014, EDSS 6.0), who was directly admitted to our intensive care unit (ICU)
on March 29th, 2020 with progressive respiratory failure and infection of the urinary
tract. She reported productive cough and anuria since the previous day. The patient
was tested positive for SARS-CoV-2 by PCR on April 29th, 2020 (Ct 36). She had been
receiving rituximab since 2014 and the last time in November 2020. Notably, the patient
had well-treated hypothyroidism, myasthenia gravis in remission, well-adjusted insulin-dependent
diabetes mellitus type 2, arterial hypertension, chronic obstructive pulmonary disease,
obesity and has smoked daily 20 cigarettes for more than 15 years. On admission, inflammatory
biomarkers (CRP 16 mg/L, interleukin-6 14.2 ng/L), cardiac parameters (CK 168 U/I,
high sensitive troponin T 29 pg/mL, proBNP 546 ng/L) and d-dimers (2.93 mg/L) were
elevated but procalcitonin (0.21 µg/L) was normal. Radiologic findings included bilateral
pneumonic infiltrates and pleural effusions. She had a B cell count of 25/µL (Ref.
80–500/µL, Supplementary Table 2) at the day of admission and tested negative for
SARS-CoV-2-specific antibodies (3.5 AU/mL; Ref. < 15 AU/mL) on April 7th, 2020, which
converted to detectable antibodies on April 29th, 2020 (71.5 AU/mL). During her stay
at our ICU she had a complicated disease course with bacterial superinfection and
severe acute respiratory distress syndrome. She was intubated on April 1st, 2020 and
subsequently received tracheotomy on April 17th, 2020 that was eventually removed
on May 4th, 2020 after hemodynamic stabilization and decreasing infection parameters.
Other complications included pre-renal failure due to volume depletion that was treated
by intermittent continuous veno-venous hemodialysis and absolute tachyarrhythmia that
was terminated by treatment with amiodaron. The patient completely recovered and was
submitted to regular ward on May 6th, 2020. We did not observe a symptomatic exacerbation
of her NMOSD and she was discharged on May 12th, 2020 (Fig. 1b).
In summary, we report on two patients who developed COVID-19 while under treatment
with rituximab due to neuroimmunological diseases. Notably, their B cell count varied
from non-detectable to markedly suppressed. We observed, that firstly only complete
B cell depletion affected antibody response against SARS-CoV-2 and secondly, virologic
control was possible in the absence of a detectable B cell response. Thirdly, neither
of the two patients showed a clinical deterioration of their underlying neurological
condition during or after SARS-CoV-2 infection. Thus, these two cases imply that immunological
factors other than B cell-mediated antibody responses are required for COVID-19 control.
However, for individuals with B cell depletion uncertainty remains towards the robustness
of viral control, the degree of immunity and risk of reinfection.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplementary file1 (DOCX 36 kb)