To the Editor,
We read with interest the report from London et al. regarding the efficacy of convalescent
plasma in the treatment of severe COVID-19 in two patients with primary immunodeficiencies
[1]. Herein, we highlight our experience of using remdesivir and convalescent plasma
to treat persistent symptomatic COVID-19 in a patient with secondary immunodeficiency
following long-term rituximab treatment.
Case Report
A 57-year-old lady presented to the emergency department on 16/4/2020 with shortness
of breath, a 2-week history of dry cough, pyrexia (38.4 °C), and raised inflammatory
markers. Chest radiography demonstrated bilateral and lower-zone peripheral air space
opacities; however, she was not hypoxic. She had a 13-year history of anti-CCP seropositive
rheumatoid arthritis, previously treated with glucocorticoids, disease-modifying anti-rheumatic
drugs, etanercept, and, most recently, 6-monthly rituximab infusions commenced in
2014. Her last dose of rituximab was on 13/3/2020, approximately 3 weeks prior to
the onset of symptoms. Serial immunoglobulin measurements are shown in Fig. 1a. The
patient had previously suffered from intermittent lower respiratory tract infections
with fully sensitive Streptococcus pneumoniae and non-typable Haemophilus influenzae
previously grown in the sputum, despite protective IgG antibody concentrations in
8 out of 12 measured pneumococcal serotypes (Supplementary Table 1).
Fig. 1
a Serial serum IgG (gray), IgA (blue), and IgM (red) measurements over time. Normal
ranges are shown by dotted lines. Asterisk “*” represents date rituximab was initiated.
b Changes in peripheral blood neutrophil count, lymphocyte count, C-reactive protein,
and temperature over the time course of disease relative to pharmacological treatments
received. Time course is relative to the first presentation on 16/4/2020. c Level
of serum IgG, IgA, and IgM anti-SARS-CoV-2 trimeric spike glycoprotein antibodies
were measured before and after treatment with convalescent plasma. Results are expressed
as a signal to the cutoff calibrator ratio with the dotted line representing the cutoff
for positivity. d In vitro SARS-CoV-2 neutralizing activity of serum from the patient
before (day 91) and after (day 106 and day 119) the administration of convalescent
plasma. Dex, dexamethasone; PCR, polymerase chain reaction; CT, cycle threshold; TMA,
transcription-mediated amplification
A diagnosis of likely COVID-19 was made, but not proven by polymerase chain reaction
(PCR) studies; the patient was discharged with broad-spectrum, oral antibiotics but
re-represented 8 days later with persistent pyrexia (39.2 °C), cough, dyspnoea, and
new diarrhea and vomiting. Inflammatory markers remained elevated and she was admitted
for treatment with intravenous antibiotics and fluids. Three nasopharyngeal swabs
taken within the first 3 days of admission returned negative results; however, radiological
progression suggested ongoing viral pneumonia; SARS-CoV-2 RNA was first detected in
a sputum sample on day 25 and subsequently found on multiple nasopharyngeal swabs
between May and July 2020.
Between May and July 2020, she was re-admitted to the hospital on four occasions with
similar symptoms, increasing oxygen requirements (peak oxygen requirements 4 L via
nasal cannula to achieve peripheral oxygen saturation of 96%; desaturation to 82%
on room air on exertion) and progressive radiological changes (Supplementary Figure
1). Blood cultures, urine cultures, sputum cultures, sputum mycobacterial PCR, and
virology for cytomegalovirus and Epstein-Barr virus undertaken during these admissions
did not identify another concurrent infection. During these admissions, she received
three separate courses dexamethasone (6 mg once daily, orally; one 7-day course; two
10-day courses) and one course of remdesivir (200-mg loading dose followed by 100 mg
once daily, 10 days, intravenously). Monotherapy with dexamethasone achieved little
objective change in physiological and biochemical parameters of infection but treatment
with intravenous remdesivir was associated with a dramatic reduction in C-reactive
protein (Fig. 1b). Twenty-four hours after the cessation of remdesivir, a rebound
increase in CRP and temperature was observed suggestive of a release of suppression
of viral replication; SARS-CoV-2 RNA remained detectable following nasopharyngeal
swabbing. Despite prolonged PCR positivity, anti-spike and anti-nucleocapsid SARS-CoV-2
antibodies were not detectable in the patient’s serum by mid-July 2020 secondary to
ongoing, complete, peripheral B cell aplasia. On day 99, the patient received two
units of convalescent plasma (275 mL/unit, units were centrally pre-screened by the
NHS Blood Transfusion Service for a SARS-CoV-2 neutralizing antibody titer greater
than 1:100). Convalescent plasma was well tolerated with rapid symptomatic improvement,
reduction in inflammatory markers, and defervescence.
Following the administration of convalescent plasma, SARS-CoV-2 PCR was not detected
on seven consecutive swabs taken between day 101 and day 119. IgG but not IgA or IgM
antibodies directed against the spike protein remained detectable in the patients’
serum 3 weeks following administration of the plasma product (Fig. 1c). A serum sample
taken 7 days after the administration of convalescent plasma showed > 95% neutralization
of SARS-CoV-2 infectivity at a 1/200 dilution compared to pre-convalescent plasma
serum (Fig. 1d). Neutralizing activity had been lost by day 119. A full description
of the neutralizing assay is available in the supplementary methods. Resolution of
plain-film radiological changes was observed by day 154 (Supplementary Figure 1).
Discussion
Adults with primary and secondary immunodeficiencies are at increased risk of morbidity
and mortality from COVID-19 compared to the general population [2]. There are limited
treatments for severe COVID-19; of the empirical treatments used in this study (dexamethasone,
remdesivir, convalescent plasma), the only dexamethasone is associated with reduced
28-day mortality in the general population [3–5]. Whether the results from these large
trials can be rationally generalized to patients with immune deficiencies is unknown.
Remdesivir is a ribonucleotide analog that inhibits the SARS-CoV-2 RNA-dependent RNA
polymerase and arrests viral RNA synthesis by acting as a delayed chain terminator
[6]. Concordant with previous case reports (Supplementary Table 2), we found the administration
of remdesivir was associated with significant improvements in immunological and physiological
biomarkers of SARS-CoV-2 infection. However, the rapid recrudescence of symptomatic
COVID-19 following the cessation of remdesivir supports the hypothesis that remdesivir
monotherapy is insufficient to support virological clearance and resolution of COVID-19
in patients with humoral immunodeficiency.
In our patient, and others treated with both remdesivir and convalescent plasma (summarized
in Supplementary Table 2), complete virological clearance and prolonged symptomatic
resolution were only achieved following the administration of convalescent plasma.
The efficacy of convalescent plasma in the treatment of COVID-19 in patients has been
reported in small case series of individuals with both congenital and acquired B cell
aplasia [7–9]. Of note, two reports demonstrate that viral persistence can occur despite
the generation of CD4 and CD8 T cell responses to viral antigens and that magnitude
of ex vivo antiviral T cell responses is augmented following the administration of
convalescent plasma [10, 11]. These data point to a non-redundant role for humoral
immunity in immunological control of SARS-CoV-2, potentially via mechanisms such as
antibody-dependent cellular cytotoxicity or opsonization, and suggest convalescent
plasma is a rational therapeutic choice for individuals with humoral immune deficiencies,
particularly when current immunoglobulin replacement products lack SARS-CoV-2-specific
antibodies [12].
However, the administration of convalescent plasma to immunodeficient patients has
been associated with the emergence of novel genomic variants within SARS-CoV-2 encoding
spike proteins that demonstrate reduced susceptibility to neutralization in vitro
[13]. Thus, combination treatments that simultaneously suppress viral RNA synthesis
and facilitate viral clearance may be appropriate in immunocompromised individuals,
to prevent the emergence of novel viral variants. A more comprehensive understanding
of mechanisms through which convalescent plasma mediates its therapeutic effect and
how these mechanisms are defective in primary and secondary immune deficiency may
allow the selection of individuals who would benefit from such interventions.
Supplementary Information
ESM 1
(PDF 4517 kb)
ESM 2
(DOCX 22 kb)