key: cord-0966227-01ki0mpd
authors: Sahu, Kamal Kant; Siddiqui, Ahmad Daniyal
title: A review on recipients of hematopoietic stem cell transplantation patients with COVID-19 infection
date: 2021-05-05
journal: Ther Adv Infect Dis
DOI: 10.1177/20499361211013252
sha: c8abab696b5fb7bb83791a5496b88ff46f61d87d
doc_id: 966227
cord_uid: 01ki0mpd

For the last few months, various geographical regions and health sectors have been facing challenges posed by the current COVID-19 pandemic. COVID-19 has led to significant disruption in the normal functioning of potentially life-saving therapies of hematopoietic cell transplant and chimeric antigen receptor therapy. As transplant physicians are gaining more information and experience regarding the undertaking of these complex procedures during the ongoing COVID-19 pandemic, we believe it is important to discuss the challenges faced, prognostic risk factors, and outcomes of COVID-19 in post-hematopoietic stem cell transplantation patients based on the available real-world data.

Hematopoietic stem cell transplantation (HSCT) is a highly complex procedure, which is performed with the intent to cure many hematological, oncological, and various genetic disorders. It involves multidisciplinary effort and a dedicated transplant team to perform HSCT. However, there are many factors that affect the immediate transplant outcome, long term survival, and quality of life of patients.

During the current pandemic, the risk of acquiring COVID-19 in transplant recipients has threatened the patient as well as the transplant team. 1 Uncertainty as to the transplant outcome, worsening of graft-versus-host disease, complex interaction of various anti-COVID-19 drugs and immunosuppressant agents, lack of blood products, and emotional breakdown of the patient and the treating staff are only a few of the many challenges being faced by our patients undergoing transplant and by the corresponding transplant team members. 2, 3 There are approximately more than a million transplant patients across the globe, with approximately 100,000 new transplantation additions every year. Hence there is significant risk for these patients to acquire this coronavirus infection. 4 International collaboration: need of the hour Various transplantation societies across the globe have come together to unite against this deadly virus and its aftermath. International experts and renowned scientists from various subspecialties have shared their individual and institutional experiences to strengthen the data collaboration so that the rest of the world could benefit from the same. 5, 6 With regard to HSCT, the European Hematology Association, European Society for Blood and Marrow Transplantation (EBMT), American Society of Hematology, and American Society of Clinical Oncology are only a few of the various societies who have collaborated at various levels to help transplant physicians across the world. 7 The latest updated guidelines from EBMT (Version 11 -6 November 2020) discussed the challenges of undertaking HSCT during COVID-19, with proposed recommendations. 8 research program which works in close association with the National Marrow Donor Program located at Wisconsin, USA. CIBMTR has launched a platform to gather the data from various transplant centers. 9 

Viral load and its significance in immunocompromised patients SARS-CoV-2 virus adherence, mode of entry, replication, and disease manifestation have been studied in detail in the last few months. 11 ACE2 and transmembrane protease, serine 2(TMPRSS2) together establish a crucial step for SARS-CoV-2 virus entry to the host cell. 12 This has also been recently studied in other, different, species as well. 13 Just like many other illnesses, COVID-19 disease has been studied for its association between viral load and infectivity/ mortality. 11 A recent study by Pujadas et al. 11 conducted in over 1000 patients found a significant difference in the mean log10 respiratory secretion viral load (5.2 copies per mL versus 6.4 copies per mL) in between the patients who remained alive versus those who had died due to COVID-19 disease. They proposed the idea that the transformation of a qualitative PCR to a quantitative assessment with viral load assessment can help in stratifying high-risk patients early in the disease course. A similar observation was noted by Magleby et al. 14 in their 678-patient data in which they found that a high viral load independently predicted higher mortality. 14 We believe that HSCT patients would certainly benefit if we could find a viral-specific quantitative prognostic parameter that can predict the COVID-19 disease course at the earliest in these immunocompromised patients. In a similar attempt, Roedl et al. 15 published a case series of six patients with HSCT or chimeric antigen receptor T-cell therapy who required intensive care unit (ICU) level of care for COVID-19 pneumonia. 15 Unlike the reports by Pujadas et al. 11 and Magleby et al., 14 they did not find any correlation to suggest that a high respiratory viral load at admission could correlate with high mortality. However, they did find a significant viremia in most of their critically ill patients. 15 In five of six HSCT patients, the viral RNA load in plasma increased over time. Also, recent studies have found a more prolonged duration of viable SARS-CoV-2 viral shedding in immunocompromised patients as compared with immunocompetent patients. 15, 16 This could be of significant importance as a prolonged isolation may be required in such patients to prevent the spread to other health care providers, medical staff, and family members. 24 reported the number of co-morbidities, chest infiltrates, and neutropenia to be significantly associated with common endpoint outcome of a higher O 2 supplementation and mortality (Table 1) . 24 

There is enough literature published so far that has confirmed thrombocytopenia, raised d-dimers, and lymphocytopenia to be associated with poor KK Sahu and AD Siddiqui journals.sagepub.com/home/tai 5 prognosis in otherwise immunocompetent patients. 32, 33 The challenging part in extrapolating the same findings to patients suffering with cancer, especially with hematological malignancies, is that these patients already have many hematological perturbations owing to their disease pathophysiology. Hence, many times it is unrealistic to predict the disease severity in this subset of patients based on the laboratory data. HSCT patients have additional challenges to tackle, but not only limited to engraftment syndrome, delayed marrow recovery, drug induced pancytopenia, graft failure and so on.

Data on pediatric population on COVID-19 is far more limited than in the adult population due to the lesser number of transplantations per year. 34 Also, the prevalence of COVID-19 is higher in the adult population when compared with children. 35 Hence our understanding of behavior of COVID-19 disease in the pediatric HSCT recipient population is limited to case reports. Jarmoliński et al. 27 reported a case in a 9-year-old girl of pre-B common acute lymphoblastic leukemia who developed COVID-19 disease during the post-HSCT period. As mentioned above, Doná et al. 10 recently reported the results from their survey involving the ERN Transplant Child members. None of the patients required ICU level of care, and no deaths were reported.

In a case series of seven patients, Sultan et al. 28 found that despite using myeloablative conditioning regimens, they did not find any significant increased mortality secondary to COVID-19 infection. They also noted that use of PTCy for graft-versus-host disease prophylaxis was associated with mild COVID-19 symptoms. The postulated that a PTCy regimen might have a shielding role against COVID-19related cytokine storm. Similarly, Kanellopoulos et al. 30 in their case series noted that patients with non-myeloablative conditioning and PTCy had milder symptoms despite other high-risk features like obesity and diabetes mellitus. In mouse models, PTCy has been found to expand FoxP3+CD4+Tregulatory cells which have shown to reduce pulmonary inflammation secondary to ARDS. 36, 37 Researchers have postulated that less severe COVID-19 infection in patients receiving PTCy could be due to abrogation of cytokine release syndrome (CRS) associated with COVID-19. This is like the concept of using PTCy in haplo-identical HSCT recipients to diminish the associated CRS. 28, 30 Hence, use of non-myeloablative treatment regimen and PTCy use has been found to have a less severe clinical course if COVID-19 is acquired. 29, 30 Patients undergoing HSCT require to be inpatients for a prolonged period. This makes them more prone to acquiring nosocomial infections. This was also found applicable for our patients with hematological malignancies who acquired SARS-CoV-2 as a part of nosocomial infection. 38 Kanellopoulos et al. 30 felt that all the patients in their study acquired COVID-19 disease via a nosocomial route. Hence it would not be unreasonable to frequently test health care providers, including the nursing staff and other transplant team members, for asymptomatic carriers of SARS-CoV-2 infection.

There is a scarcity of data on outcome of patients with HSCT who get infected with COVID-19.

So far, the majority of the available information is based on reports from the individual institutions. As more transplant physicians are now resuming normal functioning of their transplant units, possibilities of absolute increase in the number of transplant patients getting infected with COVID-19 is expected to rise. While our understanding about COVID-19 has improved dramatically, a special population such as HSCT patients remains at high risk and needs special attention.

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