key: cord-1011056-eu7lshf1
authors: Horiuchi, Hiroshi; Sasaki, Hiroaki; Miyazaki, Kazuhito; Miyata, Nobuyuki; Yoshimura, Yukihiro; Tachikawa, Natsuo
title: Recovery from severe persistent COVID-19 without evidence of an anti-SARS-CoV-2 antibody response in a man with mantle cell lymphoma treated with rituximab
date: 2021-11-25
journal: J Infect Chemother
DOI: 10.1016/j.jiac.2021.11.018
sha: ed9531f6ad2e22857f50fe970c2b417d8d892fcc
doc_id: 1011056
cord_uid: eu7lshf1

Lymphoma has been reported to worsen the prognosis of COVID-19 partly because it disturbs the normal production of antibodies. We treated a man with mantle cell lymphoma treated with rituximab, who developed severe COVID-19 with viral shedding that lasted for 78 days. He stayed in the intensive care unit for 28 days and did not respond to any treatment against COVID-19. His increased oxygen demand at rest eventually resolved despite the absence of anti-SARS-CoV-2-IgG. This case illustrates that recovery from COVID-19 can occur without antibody production, and that even patients with an inability to produce antibodies can recover from severe COVID-19. It also illustrates that lymphoma patients who develop severe COVID-19 while on rituximab therapy can recover from a prolonged viral shedding state if the acute lung injury can be overcome.

Lymphoma has been reported to worsen the prognosis of coronavirus disease (COVID-19) because its non-functional lymphocytes and the depletion of normal J o u r n a l P r e -p r o o f lymphocytes by chemotherapy leads to immune dysfunction [1] . Given the high efficacy of COVID-19 vaccines [2] , neutralizing antibodies must be advantageous for recovery from COVID-19. However, the immune mechanism related to the eradication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. We report a case of severe COVID-19 in a man with mantle cell lymphoma (MCL) that had been treated with rituximab, who recovered without a significant increase in anti-SARS-CoV-2 antibodies, after being PCR positive for 78 days.

A 75-year-old man who was on maintenance therapy for MCL visited our hospital with a 2-day history of fever. He had been given rituximab 3 months previously.

He tested positive for nasopharyngeal SARS-CoV-2 antigen, and was hospitalized considering his hematological malignancy (day 2). He tested positive for nasopharyngeal SARS-CoV-2 PCR test the next day (cycle threshold (Ct) value: E14.11).

Dexamethasone 4 mg was started on day 6 for his persistent fever up to 38℃.

On day 10, he started to require oxygen therapy (3 L/min by nasal cannula). On day 11, his oxygen demand increased to 10 L/min using a non-rebreathing mask. Nasal high-flow therapy (50 L/min, FiO2: 0.50) was started on the same day. Administration of remdesivir (200 mg on day 1, followed by 100 mg administered daily on days 2 through 10) for 10 days, and steroid pulse therapy (methylprednisolone 1 g for 3 days) was started. His respiratory failure did not improve, and he was admitted to the intensive care unit (ICU) on day 15. After that, intravenous immunoglobulin therapy (IVIG) 12.5 g was administered once a day from day 21 to 25; he was given a second 10-day course of remdesivir from day 27, ivermectin 12 mg single administration on day 29, and interferon beta-1b (IFN-β) 9.6 million IU on alternate days from day 30 to 42 were administered ( Fig. 1 ). Tapered methylprednisolone was administered until day 36.

Despite these therapies, his respiratory condition did not improve significantly.

The SARS-CoV-2 PCR test remained positive, and COVID-IgG (Abbott SARS-CoV-2

IgG test), which is an anti-SARS-CoV-2 nucleocapsid protein antibody, did not become elevated ( Computed tomography (CT) on day 49 (oxygen demand: 1 L/min) revealed worsening bilateral ground-glass opacity and reticular shadows compared to that on day J o u r n a l P r e -p r o o f 15 (Fig. 2) . Despite the CT findings, his respiration status continued to gradually improve.

The PCR test result was negative for the first time on day 76. Anti-SARS-CoV-2 spike protein antibody (Abbott SARS-CoV-2 IgG II Quant test) was detectable on day 73 slightly increased, but was below the cutoff. On day 78, the PCR test was positive once again, but on days 80 and 84, two consecutive negative PCR test results were confirmed.

His SARS-CoV-2 IgG remained negative until day 86. His need for supplemental oxygen at rest disappeared on day 87. He was transferred to another hospital for intensive rehabilitation on day 89. Anti-SARS-CoV-2 antibody tests remained negative throughout the course of his illness.

This case illustrates two clinical issues. First, MCL patients on rituximab therapy who develop severe COVID-19 can become SARS-CoV-2 PCR-negative after being persistently positive for a prolonged period. Second, the patient recovered without any increase in anti-SARS-CoV-2 IgG, which illustrates that lymphoma patients who develop severe COVID-19 while on rituximab therapy can recover from a prolonged viral shedding state if the acute lung injury could be overcome.

Several cases of prolonged PCR positivity have been reported in patients with lymphoma. One lymphoma patient was found to be SARS-CoV-2 PCR positive on day 156, when he was readmitted due to progression of his lymphoma, but without any symptoms related to COVID-19. This patient received home hospice care and did not have any subsequent negative PCR test result [3] . Another patient with a history of autologous stem cell transplantation for lymphoma and non-severe COVID-19, who was given CP on day 40, remained PCR positive for 74 days [4] . Negative PCR test results

were not confirmed, but the patient improved clinically. Poor outcomes of hematooncology patients with COVID-19 have been reported [5] , while B-cell depletion may also provide an explanation for the moderate symptoms, as the lack of antibodyproducing B cells may prevent activation of the complement system [6] . Although survival of COVID-19 patients with hematologic malignancies who have been given rituximab therapy has been reported [7] , poor outcomes have also been reported in MCL patients who develop COVID-19 while on rituximab therapy [8, 9] . Despite the lack of antibody-producing B cells, our patient had severe symptoms and was considered to have showed T-cell immunity against SARS-CoV-2 [11] . Another case report described the recovery of a patient with nodal marginal zone lymphoma who developed COVID-19 while on rituximab therapy [6] . The patient had a protracted disease course, which was thought to be due to the B-cell depletion. The patient had an adequate number of CD4+ and CD8+ T cells, and the T cells might have contributed to the control of infection. The eradication of the virus in our case might have been achieved by the same mechanism.

Regardless of the immune mechanism, the clinical course in our case suggests that COVID-19 might not become chronic even in patients with severe immunodeficiency who are unable to produce antibodies.

The presence of neutralizing antibody is thought to be essential for preventing COVID-19, given that COVID-19 vaccines have been shown to be effective at preventing the disease [2] . However, as our case indicated, the inability to produce sufficient antibodies does not necessarily lead to the inability to eradicate SARS-CoV-2. A few studies showed that B-cell depletion and a defective humoral immune response may have a limited impact on the clinical outcome of COVID-19 [7, 12] . Another study evaluated serological and T-cell responses after complete COVID-19 mRNA vaccination in hematooncology patients, and found that anti-CD 20 treatment was an independent predictor for seroconversion. Notably, 74% of the seronegative patients had a T-cell immune response [13] . These studies indicate that neutralizing antibodies are not always necessary for SARS-CoV-2 eradication. At the same time, our patient's clinical course suggests that host immune response against SARS-CoV-2 could be more related than the viral toxicity itself to the development of COVID-19, considering that prolonged viral shedding did not keep causing severe lung injury after the initial aggravation of the disease.

In conclusion, a man with immunodeficiency due to being given rituximab J o u r n a l P r e -p r o o f 

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We thank Tomonori Nakazato for making plans to treat the patient with convalescent plasma.

The authors received no funding to write this report.

The authors have no conflicts of interest to declare.