Incidence, Risk Factors and Clinical Impact of Sars-Cov-2 Prolonged Viral Shedding in Patients Diagnosed with Hematologic Malignancies
Authors: Jimenez Moraima , Navarro Garces Víctor , Medina Irene , Andres Cristina , Martinez-Gallo Monica , Medina Daniel , Anton Andres , Albasanz-Puig Adaia , Cabirta Touzón Alba , Pérez González Ana , Serna Angel , Iraola-Truchuelo Josu , Pumarola Tomás , Hernandez Manuel , Ruiz Camps Isabel , Valcarcel Ferreiras David , Crespo Marta , Esperalba Juliana , Bosch Francesc , Costa Pau Abrisqueta 
Published: December 2023

Patients with hematologic malignancies (HM) infected by SARS-CoV-2 present a higher risk of prolonged viral shedding, severe infection and mortality. However, data regarding clinical outcomes and viral evolution of prolonged COVID-19 in HM are still scarce.
Our aim was to describe the incidence, risk factors, clinical outcomes and viral evolution of the protracted SARS-CoV-2 infection in patients with HM.
We collected clinical data and respiratory samples of patients with HM who consulted at Vall d´Hebron Universitary Hospital and were diagnosed with a laboratory-confirmed SARS-CoV-2 infection between March 2020 and March 2023.
Prolonged COVID-19 was defined as a positive real-time reverse transcription polymerase chain reaction (rRT-PCR) with a cycle threshold (Ct) &lt;35 beyond 30 days since microbiological diagnosis with the same genotyped viral variant. Whole-genome sequencing of the virus was performed following the ARTIC, v4.1 protocol on a MiSeq platform.
We considered an exacerbation of persistent COVID-19 the reappearance of symptoms and/or a positive SARS-CoV-2 rRT-PCR after initial clinical improvement or a previous negative rRT-PCR.
Results: Among a total of 400 patients with HM developed COVID-19, 269 patients (67.25%) were eligible for prolonged COVID-19 assessment, whereas 52 patients (13%) died due to COVID-19 before day 30 and 79 patients (19.5%) did not have follow-up rRT-PCR. Prolonged COVID-19 was documented in 126 of 269 evaluable patients (46.8%) with a median time of rRT-PCR positivity of 60 days (IQR 43-95).
Median age of patients with prolonged COVID-19 was 68 years and 46.8% were female. The main HM was lymphoma (58.7%), the majority of patients were under active treatment (78.6%), and the most frequent active therapy was anti-CD20 monoclonal antibodies+/- chemotherapy (25.4%).
In the univariate analysis, active treatment with bispecific T-cell engagers antibodies (BiTEs) (OR 9.2; p=0.048) and anti-CD38 monoclonal antibodies (mAb) (OR 4.9; p=0.02), heavily pretreated patients (&gt; 2 previous lines of therapy) (OR 3.1; p=0.02), and severe/critical acute COVID-19 (OR 7.4; p=&lt;0.01) were significantly associated with prolonged viral shedding.
Vaccination (OR 0.2; p=&lt;0.01) and the development of an optimal humoral vaccine-induced immunogenicity (anti-spike IgG &gt;260 BAU/mL) (OR 0.1; p=&lt;0.01) were significantly associated with an inferior risk of developing prolonged COVID-19.
In the multivariate analysis, active treatment with anti-CD20 mAb, BiTEs, and BTK inhibitors; lack of vaccination; an impaired humoral vaccine-induced immunogenicity and severe acute COVID-19 remained significantly associated with prolonged COVID-19 (Figure 1). CAR T-cell therapy also showed a trend to develop prolonged COVID-19 but did not reach statistical significance (OR 14.4; p=0.08).
Prolonged COVID-19 clinical spectrum in HM ranged from a chronic asymptomatic infection in 29.4% of cases (37/126) to severe infection and COVID-19 related death in 16.7% of cases (21/126).
During prolonged COVID-19, 51.6% of patients (65/126) experienced an increase in the severity of the infection, 54% (68/126) patients suffered a delay/interruption of their hematologic treatment, and 22.2% (28/126) had to suspend it indefinitely. A 55.6% of patients (70/126) experienced an exacerbation of persistent COVID-19 with a median of 1 episode (IQR 1-2) per patient. Through those exacerbations, 84.3% (59/70) required hospital readmission with a median of 17 days of length of stay (IQR 9-27).
To treat prolonged COVID-19, 55.6% of patients (70/126) required a median of 1 course of antiviral treatment and 31% (39/126) received convalescent plasma. Of note, 37.3% of prolonged COVID-19 patients (47/126) developed a pneumopathy being organizing pneumonia the most frequent one in 28.6% (36/126) of cases. Finally, data of the kinetics of viral load and intra-host viral mutations in prolonged COVID-19 patients with a positive rRT-PCR beyond 90 days will be available for the congress.
In conclusion, prolonged COVID-19 is frequent in patients with HM and clinical repercussion are severe. Patients with risk factors for prolonged viral replication, particularly those with a suboptimal humoral vaccine-induced immunogenicity and acute severe disease, require a personalized diagnostic, therapeutic and follow-up.