key: cord-0704606-h6ejt5bw
authors: Furlan, Anna; Forner, Gabriella; Cipriani, Ludovica; Vian, Elisa; Rigoli, Roberto; Gherlinzoni, Filippo; Scotton, Piergiorgio
title: DRAMATIC RESPONSE TO CONVALESCENT HYPERIMMUNE PLASMA IN ASSOCIATION WITH AN EXTENDED COURSE OF REMDESIVIR IN FOUR B-CELL DEPLETED NON HODGKIN LYMPHOMA PATIENTS WITH SARS-COV-2 PNEUMONIA AFTER RITUXIMAB THERAPY
date: 2021-05-21
journal: Clin Lymphoma Myeloma Leuk
DOI: 10.1016/j.clml.2021.05.013
sha: 909b4c0f3573d1ac6ddbb794411ba6bc9bb63534
doc_id: 704606
cord_uid: h6ejt5bw

nan

Coronavirus disease 2019 (COVID-19) is an emerging pandemic disease caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) first identified in December 2019.

Few treatment options are currently available, including Remdesivir, an inhibitor of the viral RNAdependent RNA polymerase, recently approved for the treatment of COVID-19 pneumonia requiring hospitalization, 1,2 and convalescent hyperimmune plasma collected from recovered COVID-19 patients. 3, 4, 5 Cancer patients including malignant lymphoma patients are at higher risk of developing a severe form of COVID-19 6 compared to patients without cancer. The safety of Rituximab in the treatment of malignant B cell lymphoma in the context of COVID-19 is unclear, and how B-cell depletion could affect antiviral immunity, including development of severe acute respiratory syndrome, is a matter of study.

The present paper reports the clinical courses and therapeutic responses to convalescent plasma in association with an extended course of remdesivir in four B cell-depleted non Hodgkin lymphoma (NHL) patients with COVID-19 disease, relapsed after a 5-day course of remdesivir and steroid therapy.

Four B-cell non Hodgkin lymphoma (NHL) patients who had recently been treated with anti-CD20 monoclonal antibody (Rituximab) in association with chemotherapy, or were receiving maintenance treatment with Rituximab alone, were admitted to our Infectious Disease Unit between December 2020 and January 2021 due to SARS-CoV-2 pneumonia (Table I) .

SARS-CoV-2 RNA was detected from nasopharyngeal swabs (NS) in all the patients. Chest X-ray and computed tomography (CT) scans documented bilateral pulmonary consolidation and peripheral groundglass infiltrates consistent with SARS-CoV-2 pneumonia. On hospital admission they all required oxygen supplementation, ranging between low and high flow rate via nasal cannula.

A 5-day course of remdesivir in association with steroid therapy was administered with resolution of fever and progressive improvement of respiratory failure. They were discharged afebrile, in good clinical conditions on steroid taper. SARS-CoV-2 in NS turned out to be negative on discharge in all cases.

On the same day of steroid discontinuation or the day after, all patients experienced relapse of fever and were readmitted to the hospital for clinical worsening after a median of 13 days (range 5-31) from the first discharge. Chest X-ray or CT scans showed worsened bilateral pulmonary ground-glass opacities. Low flow oxygen support via nasal cannula was required in all cases. SARS-CoV-2 turned out to be positive in NS in only one patient. In the remaining three, viral RNA was detected from low respiratory tract samples (sputum or bronchoalveolar lavage).

Neutralizing SARS-CoV-2 antibodies were undetectable in all cases by rapid immunochromatographic assays. After obtaining informed consent and medical authorisation, three doses (300 ml each) of convalescent plasma were infused in association with remdesivir therapy, which was extended for 10 days.

As shown in Figure 1 , defervescence was observed after a median of 1.5 days (range 1-2 days) after administration of convalescent plasma in the absence of steroid therapy. SARS-CoV-2 RNA in NS or BAL samples progressively declined and turned negative after a median of 10.6 days (range 10-12) after treatment. C-reactive protein levels consistently decreased significantly over time.

No clinical relapse was observed after a median follow-up of 34.5 days (range 24-55) in the patients analysed.

The four patients here described exhibited similar and peculiar clinical and serological courses.

An initial infection, ranging from mild to moderate in severity, was followed by transient negativization of Prolonged COVID-19 course and initial "false negative" test results were previously reported in a patient with marginal zone NHL and B cell depletion after Rituximab maintainance. 7 We postulate that the negative results reported 10-20 days after previous positive tests might represent the effect of an actual response to remdesivir in the context of partial immunological control, rather than "false negative" results. This is supported by observation of early remission of symptoms, although transient and restricted to steroid therapy duration.

Time to ultimate negativization of PCR appears to be significantly prolonged compared to general population, ranging from 33 and 77 days. Total hospitalization duration was also considerably longer (range 17-38 days) compared to the general population (median 12 days). 8 None of the patients required ICU admission and/or mechanical ventilation; severe complications such as stroke, myocardial infarction and liver failure were not reported. Of note, 2 out of 4 patients were diagnosed with deep vein thrombosis, representing relapsing thrombotic events in both cases. The high incidence of thrombotic complications in this setting might be related to hypercoagulability secondary to cancer treatment and/or lymphoprolipherative disease itself; pre-existent congenital thrombophilic conditions, though, were not assessed and cannot be ruled out.

Prolonged disease course is consistent with serological findings in the patients analyzed. Most of immune competent COVID-19 patients show a seroconversion 8-14 days after diagnosis. 9 In line with a previous reporting, 7 our patients showed no IgM antibody response evaluated by rapid immunochromatographic assay and absent/inadequate response in terms of SARS-CoV-2 anti-spike IgG production (range 0.01 -0.05 UI/ml) 40-74 days after initial symptoms.

Of note, clinical and serological courses were similar in the 4 patients independent of baseline immunoglobulin (Ig) levels. Only one showed severe hypogammaglobulinemia involving IgG, IgA and IgM, another a selective IgA deficiency with unmeasurable IgA levels preexistent to treatment; in a third patient Ig levels were within normal limits. A common finding was a profound B-cell depletion secondary to Rituximab treatment on immunophenotyping of lymphocyte subpopulations; in addition, T CD4+ cell counts and TCD4+/TCD8+ ratio turned out to be reduced in 2 out of 3 patients analyzed. B-cell lymphopenia translates into low protective antibody production by effector B cells, as well as impaired development of virus specific memory B cells responsible for faster antibody production in subsequent infections. In the presence of severe humoral immune deficiency, a prominent role of T cell-mediated immune responses can be postulated in this specific setting of patients. Emerging studies suggest that a majority of patients develop a strong T response, both CD4+ and CD8+, and some have a memory phenotype, potentially responsible for longer term immunity. 10 Rituximab therapy and drug-related impairment of primary and secondary humoral response may, thus, increase the risk of early relapse of symptoms after apparent clinical and microbiological recovery as well as increase the risk of reinfection. This suggests low threshold for repeat testing, including high sensitivity methods (PCR on sputum or BAL and/or blood, chest CT scan), in order to allow timely treatment of patients and guide protection measures for health care staff even shortly after or in the presence of initial negative results.

Consistently, assessment of infection resolution should rely on high sensitivity methods such as PCR in low respiratory tract samples, especially in those patients experiencing a protracted course of disease, due to low sensitivity of PCR in NS in this setting. As previously showed, serologic results are of limited use in B-cell depleted patients and have to be interpreted cautiously.

Circulating SARS-CoV-2 RNA was detected in one patient the day after onset of symptoms. A previous report of an immune compromised AML patient 11 illustrated that SARS-CoV-2 viremia inversely correlates with anti-SARS-CoV-2 antibody production and that antibody detection coincides with viral clearance in plasma. Viremia can be detected in an early phase of infection, even prior to the onset of symptoms and detection of SARS-CoV-2 by PCR in NS. Based on these observations, we advocate the potential of viremia detection as a diagnostic tool for early diagnosis in immunocompromised patients in which delayed or inadequate antibody production is expected. Determination of SARS-CoV-2 specific T cells has also been proposed as an alternative to seroconversion in patients treated with Rituximab. 7 Adaptive immunity impairment has turned out to correlate with dramatic responses in terms of viral clearance and improvement in clinical and laboratory inflammation markers to convalescent hyperimmune serum, which may, therefore, represent a potential therapeutic option in this specific setting of immune compromised patients developing severe COVID-19 disease.

A recent open label, randomized, multicenter trial did not show a significant difference in terms of efficacy between a 5-day course as compared to a 10-day course of remdesivir in patients with severe COVID-19 disease not requiring mechanical ventilation. 2 As shown in figure 1 all patients analysed experienced an initial clearance of the virus concurrent with resolution of symptoms followed by virological and clinical relapse. Unlike immune competent patients, none of these B-cell depleted patients actually achieved complete SARS-CoV-2 clearance after the 5-day course of remdesivir first administered . The infusion of convalescent plasma in association with a 10day course of remdesivir finally lead to complete viral clearance and COVID-19 disease resolution.

We therefore propose an extended course of antiviral therapy in B-cell-depleted patients aimed at achieving a sustained viral clearance.

In the lack of specific convalescent serum, high dose IV Immunoglubulin administration could also be beneficial, as previously reported by Kos Another issue is the potential emergence of viral mutations. It is plausible that impaired viral clearance due to inadequate and delayed antibody response may favor the emergence of viral mutations.

The incidence of mutations and their causative role in relapse and prolonged clinical course in immune compromised patients need to be explored.

In our small series, cancer activity in terms of persistent/progressive disease does not seem to have played a role in compromising immunity and affecting COVID-19 disease course, since all patients reported were demonstrated to be in a complete remission state of disease. Moreover, clinical behaviour and microbiological findings were similar independent of NHL grade and subtype (follicular NHL had been diagnosed in half of patients and diffuse large B cell lymphoma in the remaining half) and independent of chemotherapy regimens administered in association with Rituximab (CHOP; CHOP+MTX; MATILDE regimen +/-radiotherapy). Similar features were previously described in a patient diagnosed with marginal NHL treated with Bendamustine plus Rituximab followed by Rituximab maintainance. 7

In conclusion, we believe that the effects of adaptive immunity deficiency in patients treated with Rituximab should be taken into account for a proper choice and interpretation of laboratory tests and for guiding appropriate therapeutical approach and protective measures. PLASMA + 10-day REM Fig. 1a, b, 

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