Key words : COVID-19, Graft-versus-host disease, Hematopoietic stem cell transplant

Introduction

COVID-19 began spreading over the world when a novel coronavirus termed SARS-CoV-2 was reported initially in Wuhan, China, in November 2019. The World Health Organization designated COVID-19 as a pandemic in March 2020.1 Because of their im-munocompromised condition from their underlying malignancies and related treatments, patients with cancer have been deemed as one of the most at-risk populations.² In particular, patients who receive hematopoietic cell transplant (HCT), who require heavy doses of immunosuppressive treatments to avoid graft failure, are at high risk of developing infections, including SARS-CoV 2.³ Hematopoietic stem cell transplant (HSCT) centers around the world have experienced many challenges since the onset of the pandemic: patients are more susceptible to COVID-19 infections acquired by the surroundings, and the disease has presented several complications in this specific population subset.⁴

Therapies included under HSCT include allogeneic, autologous, and CAR-T-cell therapy. Among these, allogeneic and autologous stem cell transplant procedures have proved to be the most life-saving therapies for patients.⁵ Autologous HSCT involves the use of progenitor cells obtained from the patient, whereas allogeneic HSCT requires a human leukocyte antigen (HLA)-matched donor, which leads to some allogeneic HSCT recipients experiencing complications like sinusoidal obstructive syndrome and graft-versus-host disease (GVHD).⁵ Graft-versus-host disease occurs when the transplanted T lymphocytes detect antigenic disparities between the recipient and the host. About 20% to 50% of the allogeneic HSCT recipients experience grade 2 or acute GVHD despite having immunosuppressive agents.⁶ Because of decreased immunity, HSCT recipients, upon contracting COVID 19, the conditions of these patients worsen, leading to higher mortality. Although immunosuppressive agents are a necessity for such cohorts, not much is known about the level of poor prognosis in the course of COVID 19.⁷

Emerging reports have claimed that the major cause of death in COVID 19 is the cytokine storm and the hyperinflammatory state associated with it.8 Therefore, immunosuppressive therapy should prove to be working positively for HSCT patients, but studies have not reported such data. Overall, most such studies have shown high mortality rates in HSCT patients who contract COVID ^19.9,10

Patient safety can be ensured by maintaining hospital records on the clinical characteristics of HSCT patients with COVID-19 infection. This will help the researchers and officials to make comprehensive guidelines to be followed at HSCT centers. In this study, we incorporated real-world data, as randomized controlled trials alone cannot give a whole view of the effectiveness of an intervention due to the controlled population, with strict adherence to exclusion and inclusion criteria. Real-world data, on the other hand, gives a more insightful and greater understanding of a patient’s journey. This systematic review tries to group all the existing study cohorts together to investigate the impact of COVID 19 disease on HSCT patients, especially focusing on GVHD, comorbidities, and the associated mortality rates.

Materials and Methods

This systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines (Figure 1).¹¹ Also, the review was registered in the International Prospective Register of Systematic Reviews (PROSPERO registration number 335023).

Data sources
For this systematic review, we extensively searched PubMed, ScienceDirect, and Google Scholar. We used the following search terms: “stem cell transplantation,” “COVID-19 pandemic hematopoietic stem cell transplantation,” “SARS-CoV 2 infection in bone marrow transplantation,” and “COVID-19 in HSCT patients.” No time limit for publication or any other such filters were applied during the search. This was a title-specific search; we ultimately selected 33 published papers in our preliminary search.

Selection criteria
To exclude any irrelevant articles, our title-specific search was followed by an abstract-specific screening. Furthermore, for full-text assessment, we applied the following inclusion criteria: (1) original reports, including retrospective and prospective observational studies, (2) reports that included COVID-19 in HSCT patients, and (3) studies reporting on GVHD, comorbidities, and mortality rates. We also applied the following exclusion criteria: (1) case series reporting on <5 patients, (2) review articles, and (3) randomized controlled trials. Full texts were then assessed based on the predetermined eligibility criteria. After a few rounds of discussion, a mutual consensus was established between the authors, with final approved from the principal investigator. We set May 31, 2022, as the cut-off date for the inclusion of the studies. We ultimately selected 12 studies for our systematic review.

Data extraction
An approved tracking sheet (Excel) from the principal investigator (and mutual consensus of the authors) was used for data extraction. The authors extracted the data and added it to the tracking sheet for baseline characteristics, clinical data, treatments given, and conclusions of each study. The spreadsheets were rechecked by the principal investigator for any discrepancies.

Quality assessment
For quality assessment of the selected publications, we used the Risk of Bias In Non-Randomized Studies of Intervention (ROBINS-1) tool (Cochrane) (Figure 2). This tool is used to assess risk of bias in systematic reviews. It covers 7 domains through which risk could be introduced in systematic reviews: confounding, selection of participants, classification of interventions, deviation from interventions, missing data, measurement of outcomes, and selection of reported results. The data were independently assessed by the authors, and a specific judgment was given for each domain level as per the guidelines of the criteria for reaching risk-of-bias judgments.

Results

This systematic review included 12 studies that reported the clinical outcomes of HSCT recipients who had COVID-19. Of the 12 studies, 9 were retrospective studies and 3 were prospective studies. In most of the reports, COVID-19 was diagnosed solely on the basis of reverse transcriptase-polymerase chain reaction (RT-PCR) tests, with 2 of these studies also including serology tests. The number of HSCT recipients in each study ranged from 28 to 382. The time period of the studies ranged from 1 month to 2 years. Interventions employed for the treatment of COVID-19 included antivirals, antibiotics, convalescent plasma therapy, and intravenous immunoglobulins. Table 1 and Table 2 list the results and summary characteristics of the studies included in this systematic review.^{2,3,9,10,12-16,18-20}

Results based on male or female patient
Sharma and colleagues conducted an observational cohort study of 318 HSCT patients and concluded that male recipients who had undergone allogeneic transplantation displayed a 4-times higher risk of death than their female counterparts.⁹ However, Ljungman and colleagues and Daudt and colleagues could not find any relation between the sex of the HSCT patients and their mortality rates.^10,13 Similarly, El Fakih and colleagues also reported that there was no association between gender and mortality in HSCT recipients diagnosed with COVID-19.¹⁷

Age
Among some studies included in our review, survival rates of patients decreased with increased age. Varma and colleagues pointed out that poor outcomes of COVID-19 were observed in HSCT patients in the higher age bracket.¹⁵ Similar results of age being the determining factor for poor outcomes of COVID-19 in transplant patients were observed by Agrawal and colleagues.16 Camargo and colleagues observed that age was a contributing factor leading to the death of transplant patients diagnosed with COVID-19.¹⁸ Similarly, Daudt and colleagues observed that children and adolescents exhibited higher survival rates.¹³ In a study on pediatric HSCT patients, Haeusler and colleagues concluded that mortality rates of adult HSCT patients were higher than rates of pediatric patients.¹⁹ Ljungman and colleagues also noted that the most important factor affecting mortality in patients was old age, probably due to comorbidities.10 In contrast to these observations, 1 study reported that age had no relation to poor outcomes of COVID-19.¹⁷

Comorbidities
It is also worth mentioning that age and comor-bidities go hand-in-hand as the risk of developing comorbidities increases as a person ages. A significant increase in mortality was observed in the case of HSCT patients showing comorbidities.¹⁰ Poor outcomes of COVID -19 in transplant recipients were observed to be associated with relapsed disease and comorbidities.² Similarly, existence of any comor-bidity was shown to significantly increase the risk of poor disease outcomes, with bacterial coinfection, neutropenia, and chronic lung disease resulting in poor COVID-19 outcomes.²⁰ Chandar and colleagues reported that pediatric patients with hyponatremia or fungal infections were at a higher risk of developing adverse events leading to death.¹² It was also found that patients who were underweight and had lymphopenia were susceptible to worse COVID-19 outcomes.¹⁵ However, Daudt and colleagues did not find any association between comorbidities and the overall survival of the patients.¹³ Along the same lines, El Fakih and colleagues did not report any link between comorbidities and poor outcomes of COVID-19 in HSCT patients.¹⁷

Graft-versus-host disease
In patients who receive allogeneic HSCT, GVHD occurs due to the activation of donor-derived T cells against the histocompatibility antigens in the patient. However, the effect of GVHD on COVID-19 outcomes is still not clearly known. Sharma and colleagues pointed out that, as a result of GVHD, patients have shown a higher risk of developing severe COVID-19.⁹ The occurrence of GVHD was found to be associated with the mortality rate post-HSCT in pediatric patients who were diagnosed with COVID-19.¹² Varma and colleagues noted a significant trend of increased mortality in patients with active GVHD compared with those with no reported GVHD.¹⁵ However, Ljungman and colleagues reported that the occurrence of GVHD did not affect the survival rate of HSCT recipients with COVID-19.¹⁰

Time between hematopoietic stem cell transplant and COVID-19 diagnosis
The effect of the time period between HSCT and COVID-19 diagnosis on poor disease outcomes and survivability of HSCT recipients has shown mixed results. Some of the studies noted that it is a determining factor, whereas others do not support this claim. Shah and colleagues reported no clear relationship between the time period between cellular therapy and COVID-19 diagnosis to poor disease outcomes or worse survival rates.² The time period between HSCT and COVID-19 diagnosis showed no links to poor disease outcomes or high mortality rates in the study conducted by Ljungman and colleagues.¹⁰ Daudt and colleagues also concluded that no significant relationship existed between the time of COVID-19 occurrence after transplant and mortality. Instead, the group reported that the initial clinical presentation substantially affected the survival rate of patients compared with patients with less serious clinical symptoms.¹³

In contrast to the above observations, Varma and colleagues reported that contracting SARS-CoV-2 infection within 1 year of transplant increased the risk of poor disease outcomes compared with patients who were infected with SARS-CoV-2 after 1 year of transplant.¹⁵ Similarly, Agrawal and colleagues reported that SARS-CoV-2 infection within 1 year from HSCT transplant was associated with poor COVID-19 outcomes.¹⁶ Sharma and colleagues also found patients who contracted COVID-19 within 1 year post-HSCT showed worse survival rate.⁹ Similar to Daudt and colleagues,¹³ Agrawal and colleagues also claimed that severe clinical representation was related to poor disease outcomes.¹⁶ In fact, El Fakih and colleagues reported that the most important factor contributing to worse outcomes of COVID-19 was the time between HSCT and SARS-CoV-2 infection. Patients who had undergone transplant 6 months before COVID-19 diagnosis exhibited higher admission rates and higher severity of the disease.¹⁷ Camargo and colleagues also noted that patients who contracted SARS-CoV-2 within 1 year of transplant showed a higher mortality rate than patients who were infected within 1 year of HSCT. The team also pointed out the importance of clinical presentation and the underlying disease severity at the time of initial consultation to be the governing factor behind poor COVID-19 outcomes.¹⁸

Transplant type
Ljungman and colleagues reported that the type of transplant did not determine the overall survival of the HSCT recipients diagnosed with COVID-19.¹⁰ Along similar lines, Daudt and colleagues also reported that the type of transplant showed no relation to survival in HSCT recipients diagnosed with COVID-19.¹³ Karatas and associates also concluded that there was no statistically significant difference between the mortality rates of autologous and allogeneic HSCT recipients diagnosed with COVID-19,¹⁴ with similar finding by Agrawal and colleagues,¹⁶ Altuntas and colleagues,³ and Camargo and colleagues.¹⁸ In addition to the type of transplant, the number of transplants also had no association with poor disease outcomes.¹⁷ However, Sharma and colleagues noted that recipient of allogeneic transplant exhibited a 4-times higher risk of mortality than patients who had autologous transplant.⁹ Therefore, it can be concluded that the type of transplant, allogeneic or autologous, does not affect the poor disease outcomes and subsequent mortality of HSCT patients.

COVID-19-associated mortality
A substantial amount of heterogeneity was observed in the mortality rates reported in the studies, ranging from 4.4% to 33.3%. A clear conclusion about the distinction between the mortality rates of allogeneic and autologous transplant patients could not be reached. Some of the studies reported a higher mortality rate for the allogeneic cohort compared with the autologous cohort.^2,15,18 Other studies claimed that autologous transplant recipients showed higher mortality rates than the allogeneic transplant recipients.^9,10,13 Therefore, the data on the impact of the type of transplant on the mortality rate are inconclusive.

Overall, cancer patients with hematologic malig-nancies showed a high risk of developing severe disease and a high mortality rate from COVID-19 compared with the healthy population.^9,10,15 This observation has not been contradicted or challenged by any of the studies included in this review. Pediatric HSCT recipients who had already undergone HSCT were also shown to be at a higher risk of developing severe COVID-19 and subsequent death.¹² A study conducted in Turkey concluded that a low mortality rate is associated with those patients whose primary disease is in remission.¹⁴

Other transplant complications
The question of how, despite taking immunosup-pressants and thus evading cytokine storm, HSCT patients still develop severe COVID-19 disease was addressed with a hypothesis that immunosup-pressed patients have a significant decrease in lung inflammation, which could be a possible reason for observed mortality.⁹ A marked reduction in lymphocyte or granulocyte count was observed among HSCT patients with SARS-CoV-2 infection.^2,10 A study on pediatric HSCT recipients described rhinocerebral rhizopus, an opportunistic fungal infection, which arises at the time of immune recovery. Children who have adequate immune reconstitution before SARS-CoV-2 infection did not develop this infection and survived.¹²

Daudt and colleagues performed a retrospective cohort study on 86 HSCT patients with confirmed SARS-CoV-2 infection in 5 regions of Brazil.¹³ This study describes the association of mortality rates with “regional effect,” which relates to only certain regions of an area experiencing a more severe form of the disease than other areas as a result of factors such as lower socioeconomic development, effect of ethnicity, hospital infrastructure, and presence of comorbidities. An increased mortality was found in the northern region of Brazil compared with the central or southern region. The investigators also reported that other clinical factors like body mass index, ABO blood typing, and conditioning regimens were not associated with patient mortality. In another study, staying on steroids, higher lactate dehydrogenase level, and high ferritin at the time of COVID-19 diagnosis were reported to worsen the COVID-19 outcomes in HSCT recipients.¹⁵

Discussion

Bone marrow transplant patients with SARS-CoV-2 infection constitute a heterogeneous group, therefore drawing conclusions from single studies with a few number of patients cannot give a holistic view of the data. Studies with larger datasets are needed so as to understand the whole effect of COVID-19 on HSCT recipients. This systematic review reported data from 12 studies, including 1505 patients who contracted SARS-CoV-2 infection after bone marrow transplant, while focusing on the mortality rate of the patients.

Most studies included in this review reported no association between male or female sex and mortality of HSCT recipients with COVID-19. However, 1 report suggested a 4-time higher risk of death in male versus female transplant recipients. Whether sex-related differences exist requires more studies as the available reports were inconclusive.

A number of studies observed a direct relationship between older age and higher mortality rates. With an increase in age, underlying comorbidities like hypertension, diabetes, chronic kidney diseases, and congestive heart disease, also could affect outcomes. The presence of such comorbidities, in addition to HSCT, can make it quite difficult for the immune system to fight SARS-CoV-2 infection. Thus, age has been related to poor survival in the HSCT cohort.^20,21 However, at the same time, El Fakih and colleagues could not find any relation between older age and poor outcomes of COVID-19.¹⁷ This can be explained by the design of the study, wherein 52% of the patients had no comorbidities. Moreover, cohort was comparatively younger and had access to advanced care in hospitals.

Shah and colleagues reported that the type of malignancy of the patient did not affect the poor outcomes of COVID-19.² This could be because, irrespective of the type of the malignancy, all bone marrow transplant patients have to take immuno-suppressants. Thus, they all have a suppressed immune system, which has been related to a more aggressive COVID-19 prognosis and mortality in patients with hematologic malignancies.²²

Patients with HSCT and GVHD or other comorbidities exhibit an additional risk of worse COVID-19 outcomes Studies on obese individuals have shown that they are more likely to develop severe COVID-19 outcomes as adipose tissue acts as a potent pathogen reservoir.²³ Because of the high glucose concentration in the bloodstream of patients with diabetes, the C-type lectin receptors constantly recognize glucose molecules, which in turn leads to a high rate of inflammation. Individuals with hypertension take medications that reduce blood pressure (angiotensin II type 1 receptor blockers and angiotensin converting enzyme inhibitors). This consequently leads to an increase in the ACE2 expression, the receptor used by SARS-CoV-2 to infect human cells.²⁴

Prior reports have shown that GVHD imposes deleterious effects on the donor T cells that were transferred with the graft.²⁵ This is because of activation-induced cell death²⁶ and their shortened survival time.²⁷ Studies have shown that GVHD impairs T-cell and B-cell function.^28,29 In a study that investigated levels of microRNA-181a and -b in peripheral blood sample of patients with acute lymphoblastic leukemia at the time of COVID-19 diagnosis prior to chemotherapy and in healthy individuals by RT-PCR, microRNA-181a and -b expression levels were significantly higher in patients with acute lymphoblastic leukemia and COVID-19 who developed acute GVHD versus healthy controls.³⁰

Some studies reported no association between the time period between HSCT and COVID-19 diagnosis and mortality in HSCT patients.^2,10,13 However, several studies noted that patients who had contracted COVID-19 within 1 year or 6 months post-HSCT exhibited a higher mortality rate.^15,16,17,18 One of the major factors governing this could be the intensity and duration of immunosuppressants administered to the patients. High-intensity admi-nistration of immunosuppressants has been known to result in high mortality rates in HSCT patients.¹⁸ Profound viremia was found in pediatric patients by Chandar and colleagues,12 which was due to the use of immunosuppressants and worse immune reconstitution.

Overall, the studies showed that mortality rates in bone marrow transplant recipients are signifi-cantly higher than rates in patients with COVID-19 and no history of HSCT. Moreover, a slight increase in the mortality rates of patients who underwent allogeneic HSCT was observed compared with patients who received autologous HSCT, but this cannot be held true for all cases. In their pooled analysis, Shahzad and colleagues concluded that allogeneic HSCT recipients (21%) had worse mortality rates than autologous HSCT recipients (17%), although the results were not statistically significant.³¹ Therefore, although it is evident that high mortality is seen among HSCT recipients, it is not clear as to which type of transplant leads to higher survivability. All of the studies included in our review noted that no relationship existed between the type of transplant and mortality in HSCT patients.

Several immunomodulatory agents, as well as antivirals, have been used to treat COVID-19 in bone marrow transplant patients. The US Food and Drug Administration approved the antiviral remdesivir for the treatment of COVID-19, especially for patients who required hospitalization. However, efficacy analyses of remdesivir have not shown good results.^32-34 Convalescent plasma therapy was also used in many parts of the world for immuno-compromised patients with COVID-19. Interestingly, lower mortality rates (6% for allogeneic, 3% for autologous) were observed in HSCT recipients who were given hydroxychloroquine and azithromycin for COVID-19 treatment than in patients who were given antivirals like remdesivir, lopinavir, acyclovir, famciclovir, or oseltamivir.

There are some limitations of our analysis. All of the studies included were rather heterogeneous in nature, and therefore they could not provide us with clear comparison arms. Because the studies were conducted in different parts of the world and at different times, information about the specific waves and the strain of the coronavirus was not included. The included studies did not mention vaccination of HSCT recipients, limiting our ability to form conclusive remarks on the effects of vaccination on disease outcomes of HSCT patients. The studies were not conclusive on the effect of the type of malignancy on HSCT recipients diagnosed with COVID-19. Intensity details of regimens (eg, transplant condi-tioning regimens, GVHD prophylaxis regimens) were heterogeneous and were not included in most of the studies. The information on the clinical complications of COVID-19, especially in regard to HSCT recipients, was limited as COVID-19 is still a comparatively new disease. The only factor posing a significant amount of risk of developing COVID-19 in HSCT is SARS-CoV-2 exposure. Therefore, after bone marrow transplant, clinic visits should be limited and medicines should be prescribed by using online tools.

Conclusions

The main takeaway of this systematic review is that recipients of bone marrow transplant experience poor COVID-19 outcomes and worse mortality rates than the general population. The second crucial finding is the identification of the risk factors related to the death of HSCT patients with SARS-CoV-2 infection. All in all, the major factors are age, underlying comorbidities or GVHD, immunosup-pressant intensity, and the type of intervention selected for COVID-19 treatment (Table 3). Moreover, we can also conclude that the time between HSCT and COVID-19 diagnosis, type of malignancy, and type of transplant do not result in a worse prognosis of COVID-19. In the absence of efficient curative treatments, prevention of the disease should be the main concern and remains the only option available. It is necessary for the concerned authorities to devise guidelines that would include strict regulations on limited clinic visits for HSCT patients and online interactions with doctors. In addition to this, social distancing, use of personal protective equipment, switching to oral therapies from intravenous therapies, and infection control at home for patients with hematologic malignancies are all the steps that are necessary for preventing transplant patients from getting SARS-CoV-2 infection. Despite advances in the field of pathophysiology and therapeutics, the prevention of COVID-19 remains the only way out of the problem. In addition, long-term outcomes of the disease should also be noted to devise better guidelines that could decrease the overall mortality of patients. Long-term outcomes should be studied to allow understanding of whether survivors of HSCT, at high risk of developing hypertension, diabetes, or any cardiovascular disease, would also show worse mortality rates compared with a healthy population. In conclusion, HSCT patients constitute a special cohort of the population that require attention and care from physicians, especially for those patients who are taking immunosuppressants during COVID-19. In the future, studies that include immunologic determinants related to the severity of the disease should be explored.

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