Implications of persistent SARS-CoV-2 infection in patients with lymphoid malignancies

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the virus responsible for the coronavirus disease 2019 (COVID-19), has infected over 221 million people worldwide since it originally emerged in December 2019.

Up to one-third of otherwise healthy people who have recovered from acute COVID-19 will continue to experience physical and cognitive symptoms. These patients are often referred to as “long haulers,” with the extended symptoms being described as “long COVID” or post-COVID-19 syndrome.

Study: Prolonged SARS-CoV-2 infection in patients with lymphoid malignancies. Image Credit: Near D Krasaesom / Shutterstock.com

In cancer patients, especially patients suffering from hematologic malignancies, there is an increased risk of developing severe COVID-19 infection, long COVID-19 syndrome, and mortality. Long COVID syndrome in these patients is characterized by extended respiratory problems and hospital readmissions which may be the result of persistent infections.

In a recent study published on the preprint server medRxiv*, scientists at Memorial Sloan Kettering Cancer Center and Cornell University in New York attempt to understand persistent COVID-19 and its implications in patients with hematologic malignancies.

Predictors for persistent SARS-CoV-2 positivity in patients with hematologic malignancies

Patients diagnosed with COVID-19 who show test positive for COVID-19 test through the reverse-transcriptase polymerase chain reaction (RT-PCR) assay for 30 days or more are classified as having chronic persistent COVID-19 infection. In the current study, patients with hematologic manifestations including lymphoid malignancies were evaluated for predictors for persistent SARS-CoV-2 RT-PCR test positivity.

The following factors were considered independent predictors for persistent SARS-CoV-2 test positivity:

• Systemic chemotherapy within 30 days before infection
• Anti-CD20 antibody therapy within 1 year before the infection
• Hematopoietic stem cell transplantation (HSCT) within 1 year before the infection

Notably, age and the presence of lymphoid malignancies were not found to be independent predictors for persistent SARS-CoV-2 RT-PCR test positivity in this patient population.

Characteristics of COVID-19 in patients with prior lymphoid malignancies

The study identified treatments provided for lymphoid malignancies as the strongest predictors of persistent COVID-19 infection. To investigate this further, 214 patients suffering from lymphoid malignancies who contracted COVID-19 were studied.

Of the 214 patients identified for this study, the majority were suffering from non-Hodgkin’s lymphoma, with the most common subtypes including chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma. Amongst this patient population, nearly half of the patients had previously received systemic therapy, some of which included:

• Anti-CD20 monoclonal antibody therapy
• Bruton tyrosine kinase (BTK) inhibitor therapy
• Autologous or allogeneic stem cell transplantation
• CD19-directed chimeric antigen receptor (CAR) T-cell therapy

The patients in the study population were in different stages of therapy when they were diagnosed for COVID-19, which ranged from active management, surveillance, and remission.

Importantly, most of these patients had severe outcomes due to COVID-19, which included hospitalization with a need for supplemental oxygen, intensive care unit admission, and mechanical ventilation. The hospitalized patients in the study population were given the hydroxychloroquine convalescent plasma, remdesivir, dexamethasone and/or other systemic steroids, intravenous immune globulin, tocilizumab, anakinra, and N-acetylcysteine.  

The fatality rate in the study population that was hospitalized was 22%, whereas 31% of the patients had extended hospitalizations. Of the discharged patients, 24% had recurrent respiratory problems and hospital readmissions. Additionally, these patients showed persistent positivity for COVID-19, thereby indicating incomplete viral clearance from their system.

Immunological parameters correlating with clinical outcomes in lymphoma patients with COVID-19

The analysis of the study population revealed that cardiovascular-related diseases, active treatment for lymphoma, and CAR T-cell therapy within one year before the initial diagnosis of COVID-19 were independent predictors of mortality.

Lymphoma patients who had COVID-19 were divided into three clusters based on their immunological laboratory findings. The correlation between the immunological characteristics of the clusters and outcomes due to COVID-19 infection was assessed.

The highest mortality rate was observed in patients in cluster 1 and was characterized by reduced levels of T-cells, elevated levels of inflammatory markers, and reduced T-cell response.

Comparatively, patients in cluster 2 had intermediate levels of T-cells and moderate levels of inflammatory markers. A majority of patients in this latter cluster had also undergone anti-CD20 therapy and exhibited a partly reduced immune response with B-cell depletion. In this cluster, an intermediate mortality rate was observed. However, hospital readmission rates were high due to persistent COVID-19 symptomatic infection.

In cluster 3, patients were characterized by low levels of inflammatory markers, normal levels of T-cells, and adequate levels of adaptive immune response that is mediated by the T-cells and B-cells of the immune system. The mortality rate was lowest in this cluster of patients.

Based on these findings, the authors aimed to identify the correlation between inflammatory markers and outcomes in COVID-19 in the study population. To this end, they found that severe lymphopenia, which is defined as low levels of lymphocytes, and depleted B-cell counts were common in lymphoma patients hospitalized for COVID-19.

Patients with severe CD8⁺ or CD4⁺ lymphopenia experienced adverse outcomes due to COVID-19. Additionally, inflammatory markers like interleukin-6 (IL-6), D-dimer, lactate dehydrogenase (LDH), C-reactive protein (C-RP), and ferritin were associated with mortality in these patients.

Immunological parameters in lymphoma patients with persistent COVID-19 infections

In the study population of lymphoma patients, there was a high incidence of persistent COVID-19, extended hospital stays, and readmissions. The authors attempted to identify the clinical and immunological parameters that correlate with persistent COVID-19 infection.

In the patients who required rehospitalization, all patients had respiratory symptoms in between readmissions. The computed tomography (CT) scans of these patients also revealed signs of a viral infection.

Patients who had undergone anti-CD20 therapy in the year prior to acquiring COVID-19 had a significantly high risk of hospital readmission. Further, low levels of CD4⁺ T-cells also correlated with an increased risk of hospital readmission in these patients.

These results suggest that, in lymphoma patients, there is reduced CD4⁺ T-cell and B-cell mediated immunity, thus resulting in a compromised immune response. This may increase the risk for persistent symptomatic COVID-19. The reduced B-cell and T-cell response may also lead to incomplete viral clearance in these patients.

Patients with persistent COVID-19 infection and incidence of viral diversity

The present study further explored if there was an occurrence of viral evolution, simultaneous infection with different COVID-19 strains, or re-infection in the lymphoma patients who exhibited persistent COVID-19.

The findings from this analysis revealed the absence of evidence for re-infection and co-infection with other variants in these patients. There is, however, evidence for persistent infection.

Further, it was found that the incidence of increased viral diversity, which arises due to mutations in the viral genome, is evident in patients with reduced CD8⁺ T-cell counts. This implies that active CD8⁺ T-cell counts may restrict the development of high viral diversity. In patients with persistent COVID-19, as well as those who have weak adaptive immunity with reduced CD8⁺ T-cell counts, the incidence of viral diversity may be high.

Persistent COVID-19 and its implication in lymphoma patients

The present study adds additional evidence to support earlier findings that lymphoma patients who develop acute COVID-19 have a higher risk of mortality and probability of developing severe outcomes. The current study also reveals that these patients may develop persistent COVID-19, which may increase their risk of transmitting this disease due to incomplete viral clearance.

More research needs to be performed to effectively characterize the immunological aspects of persistent COVID-19 in lymphoma patients. Based on the present findings, the scientists in also recommend passive immunoprophylaxis, which involves the administration of antibodies/lymphocytes that have been generated in another person, to prevent COVID-19 in lymphoma patients.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Maheswari Rajasekaran

Maheswari started her science career with an undergraduate degree in Pharmacy and later went on to complete a master’s degree in Biotechnology in India. She then pursued a Ph.D. at the University of Arkansas for Medical Sciences in the USA.