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ASH Agenda for Hematology Research

ASH COVID-19 Research Agenda for Hematology

In response to the emergence of hematologic complications from COVID-19 infection, ASH has developed the COVID-19 Research Agenda in Hematology. This living document represents fundamental questions that experts in hematology and blood research deem of critical importance to researchers, physicians, and patients.

With the emergence of new understanding of COVID-19 and the hematological implications of this infection, and as new questions arise, ASH will continue to revisit and update this agenda.

Data are emerging that COVID-19 infection can result in coagulopathy in severely ill patients, and there are reports of an increased risk of clinical and subclinical thrombosis in the setting of severe COVID-19 disease. Clinically, controversy around the role of pre-emptive or sequelae-based anti-coagulation therapy in the treatment of COVID-19 disease has resulted in inconsistent and unvalidated treatment protocols and a paucity of rigorous observational and clinical trial data. Moreover, the risk factors for arterial thrombosis, venous thrombosis, pulmonary embolism/thrombosis , or other coagulopathy in the setting of COVID-19 infection remains unknown.

Incidence of COVID-19 associated coagulopathy, including clinical and subclinical thrombosis, and risk factors for thrombotic and coagulopathic sequelae. 
Effect of COVID-19 on endothelium endothelialitis and its anticoagulant properties.
Underlying biology of coagulopathy/thrombosis in COVID-19 patients.
Treatment of VTE, PE, and arterial thrombi in COVID-19 patients. Observational studies and clinical trials which can be used to develop evidence-based guidelines for thrombosis treatment and prevention in patients with COVID-19 disease.

Given race as a risk factor for COVID-19 and sickle cell disease (SCD), it is important to look at potentially vulnerable population of hematology patients.

How do underlying conditions, such as vascular dysfunction, contribute to higher infection rates and deaths? Do these underlying factors contribute to heme-related adverse effects? This is particularly critical in the SCD patient population. 
How does access to testing, care, and medication impact COVID-19 disease diagnosis, incidence, and severity? Are there specific populations with a high incidence of hematologic disorders where this is particularly evident?
What is the underlying biology contributing to these outcomes? Are there biomarkers or other indicators that can identify those who may exhibit worse infections and outcomes?
What are the mechanisms (susceptibility, immunobiology) underlying the low incidence of COVID-19 in children under twelve and under eighteen years old?

Hematologic malignancies are associated with perturbations of both innate immunity and adaptive immunity. The impact of lymphomas, myeloma, acute and chronic leukemias, and the effects of their treatments on the response to COVID-19 are poorly understood. Conversely, the inflammatory effects of COVID-19 on these conditions are not well-defined.

 How do hematologic malignancies and the treatment of hematologic malignancies affect the immune response to COVID-19? Do current or prior chemotherapy and/or immunotherapy affect antibody testing and other biomarkers of response to COVID-19? What is the balance of risks and benefits associated with maintenance therapies, such as rituximab or immunomodulatory treatments, with respect to COVID-19?
 Do patients on immunomodulatory therapy have differential capacity to mount or to curtail the immune response that contributes to the morbidity/ mortality of COVID-19?
Do tyrosine kinase inhibitors, JAK inhibitors, and/or BTK inhibitors increase risk for COVID-19 infection and/or affect COVID-19 disease severity? Conversely, do these agents lessen the impact of cytokine release syndrome (CRS), and do they alter biomarkers of the CRS-like syndrome?

The interplay between hematopoiesis/immune function and viral infections, including COVID-19, are complex and incompletely understood. Moreover, it is clear that specific hematopoietic parameters, including leukopenia, and hematologic disorders are risk factors for developing severe COVID-19 disease. It is paramount to investigate the critical interplay between the hematopoietic compartment and COVID-19 infection, and to determine how hematopoietic disorders impact COVID-19 pathophysiology and disease severity.

The relationship between hematopoietic function and the response to COVID-19 infection.
The impact of COVID-19 infection on hematopoietic function including in stem/progenitor cells, megakaryocytes, and immune effector cells.
How hematopoietic disorders impact COVID-19 pathophysiology and disease severity.
The incidence and severity of COVID-19 in immune compromised patients including patients undergoing and surviving stem cell transplantation.

Increased inflammatory mediators, including circulating cytokine levels, has been observed in severely affected COVID-19 patients and limited studies suggest that increased inflammatory cytokine levels are associated with adverse outcome. Moreover, there are parallels between severe COVID-19 disease and inflammatory toxicities, including cytokine release syndrome (CRS), a cytokine mediated inflammatory syndrome commonly seen in patients treated with immune-based cancer therapies. Likewise, pediatric patients in rare cases are experiencing an unusal inflammatory response akin to Kawasaki syndrome. Our community has expertise in the basic biology of CRS and ASH has been involved in the development of treatment algorithms for CRS and inflammatory toxicities. It is likely there are many parallels and lessons to be learned which can be used to inform the treatment of inflammatory sequelae in the setting of COVID-19 infection.

Biological basis of inflammatory mediated sequelae in setting of COVID-19 disease.
Biological determinants to development of CRS and ARDS in the presence of SARS-coV2 virus. Do certain genetic variants predispose COVID-19 patients to worse outcomes?
What is the underlying biology contributing to the Kawasaki-like syndrome in pediatric patients?
What co-morbidities or genetic predispositions predispose to or exacerbate the inflammatory disease seen in a subset of children with COVID-19 infection?
Do underlying comorbidities, including hematologic disorders, impact the severity of disease and development of an aberrant inflammatory response in patients with COVID-19 disease?
Preclinical and clinical therapeutic studies aimed to attenuate the aberrant inflammatory response in COVID-19 disease.
Preclinical and clinical studies aimed at defining and augmenting the virus-specific immune response (beyond the humoral response) to develop targeted strategies to enhance anti-viral activity via innate and/or adaptive immune responses without inducing aberrant inflammatory responses.

Extrapolating from experience with prior viral outbreaks, studies evaluating efficacy of convalescent plasma, or concentrated COVID-19 H-Ig, are being widely undertaken across US and international blood centers. There is a critical need to understand the value of this approach and how to use, test, and optimize this therapy.

How do we identify the appropriate donors? When is the best time to collect plasma from previously infected donors? What is the optimal antibody titer? How long is the titer maintained?
Which patients will benefit the most from this kind of therapy, and when should convalescent plasma be given for maximal benefit?
What is the characterization of the immune response to COVID-19. Are patients developing memory T cells or neutralizing antibodies?
Can convalescent plasma be used to generate passive immunization within the population?
How can responses to convalescent plasma or concentrated COVID-19 H-Ig be predicted?
Is there an asymptomatic COVID-19 viremia and can it be transmitted by blood transfusion?