COVID‐19 outcomes in haematopoietic cell transplant recipients: A systematic review and meta‐analysis

Abstract Up‐to‐date information on coronavirus disease 2019 (COVID‐19) outcomes and risk factors in haematopoietic cell transplantation (HCT) recipients is required to inform on decisions about cancer treatment and COVID‐19 mitigation strategies. We performed a meta‐analysis to address this knowledge gap. All studies with at least five patients who reported COVID‐19‐related deaths in HCT recipients were included. The primary outcome was COVID‐19‐related death. Secondary outcomes were COVID‐19‐related mechanical ventilation (MV) and intensive care unit (ITU) admission. The cumulative COVID‐19‐related death rate among HCT recipients was 21% (95% confidence interval [CI] 18%–24%), while MV and ITU admission rates were 14% (95% CI 11%–17%) and 18% (95% CI 14%–22%), respectively. Subgroup analysis showed higher death rates in patients who developed COVID‐19 within 12 months of HCT (risk ratio [RR] 1.82, 95% CI 1.09–3.03), within 6 months of receiving immunosuppressant drugs (RR 2.11, 95% CI 1.38–3.20) or in the context of active graft‐versus‐host disease (RR 2.38, 95% CI 1.10–5.16). Our findings support the idea that HCT should remain an integral part of cancer treatment during the COVID‐19 pandemic but also highlight the need to prioritise preventative measures in those patients who are at increased risk of adverse COVID‐19 outcomes.

recent studies have shown that HCT recipients produce a less effective immune response to COVID-19 vaccines compared to the general population [9][10][11]. In light of these considerations, we performed a systematic review and meta-analysis to quantify the clinical outcomes of HCT recipients with COVID-19, as well as a comprehensive subgroup analysis to determine clinical factors associated with adverse outcomes.

METHODS
This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [12] and the Joanna Briggs Institute (JBI) guidelines.

Inclusion criteria
All studies reporting COVID-19 outcomes in HCT recipients were screened, and all those reporting COVID-19-related deaths in cohorts of at least five patients were selected irrespective of whether they involved paediatric (age <18 years old) or adult (age ≥18 years old) patients.

Search strategy
We identified relevant studies using the PubMed and Embase databases. We also sought preprint articles from medRxiv and bioRxiv, as well as conference proceedings from relevant international scientific meetings organised by the American Society of Clinical Oncology, December 2021. In addition, reference lists of studies, systematic reviews, narrative reviews and case reports were also scrutinised for eligible studies.

Study selection
Two reviewers (Yeong Jer Lim and Umair Khan) independently evaluated all titles and abstracts identified through the initial search and excluded studies that clearly did not meet the inclusion criteria. The full texts of the remaining studies were evaluated for eligibility, and any differences of opinion were resolved by discussion.

Data extraction
Using a preformulated template, two reviewers (Yeong Jer Lim and Umair Khan) independently extracted the following data: study characteristics (author, centre(s), region, inclusion period),

Risk of bias assessment
All included studies were independently assessed for risk of bias by two reviewers (Yeong Jer Lim and Umair Khan) using the JBI critical appraisal checklist for studies reporting prevalence data [13] (Table S1).

Study selection
The results of the literature search are summarised in Figure 1.
Through a systematic search strategy, we identified 1634 records, of which 94 records were assessed in full text for eligibility. In total, we found 36 records reporting 2141 patients, all in English and published between January 2020 and December 2021, which met the predeter-mined inclusion criteria. Conversely, 58 records were excluded because they did not meet the inclusion criteria.

Risk of bias assessment
Using the JBI checklist for prevalence studies, we identified 25 (69%) studies with a low risk of bias and 11 (31%) studies with moderate to high risk. The results for the risk of bias assessment and its justification are summarised in Table 1. When assessing for publication bias, asymmetry was seen in the funnel plot ( Figure S1), with Egger's test (p = 0.001) showing the presence of significant publication bias in the included studies.
Information on COVID-19-related deaths in relation to the use of immunosuppressant drug treatment to prevent GvHD was available in 339 patients from 12 studies. The death rate was significantly higher among patients who developed COVID-19 within 6 months of receiving pharmacological immunosuppression than among those patients whose immunosuppression had been discontinued more than Notably, we did not observe any significant differences in the  Figure S4).

Sensitivity analysis
Sensitivity analysis showed that the cumulative COVID-19-related death rate was not significantly affected by excluding studies with moderate or high risk of bias or with a low sample size (n < 10) or by excluding paediatric (age ≤18 years old) HCT recipients or those without laboratory confirmation of SARS-CoV-2 infection ( Figure S5).

DISCUSSION
To our knowledge, this meta-analysis, which utilised published data involving 2141 patients from 36 studies in four different continents, is the first to examine COVID-19 outcomes in HCT recipients specifically.   Interestingly, we found no statistically significant difference in the rate of COVID-19-related death between males versus females, allogeneic versus autologous HCT recipients, or HCT recipients aged ≥50 years versus <50 years. We believe the latter observation should be interpreted with caution for two reasons. First, due to inconsistency in reporting patient age groups, we were only able to obtain this information in 208 patients from six studies, which represents only 9.7% of the HCT recipients included in this review. Second, since age is a continuous variable, the risk of COVID-19-related death may vary significantly depending on which age cutoff is used. We chose a value of 50 years, as it was close to the median age of HCT recipients in most of our included studies. However, it may not have been optimal in separating patients into two groups based on COVID-19 outcomes.
The comparable COVID-19-related death rate between allogeneic and autologous HCT recipients is also surprising given the increased risk of posttransplant-related complications and the degree of immunosuppression associated with allogeneic HCT. This observation was also supported by the two largest multicentre studies [7,8] of COVID-19 outcomes in HCT recipients to date, which showed no significant difference in the overall survival between allogeneic and autologous HCT recipients at 4-6 weeks following COVID-19. We suspect that these adverse risk factors associated with allogeneic HCT could be offset by the increased age generally found in autologous HCT recipients within our cohort of patients (where available, the median age among allogeneic HCT recipients ranged between 10 and 64 years old, while in autologous HCT, it was 40-65 years old). Furthermore, the variations in comorbidities and HCT indications between both HCT types may also have contributed to this observation, although we did not have sufficient pooled data to make any meaningful analysis in these two areas.
We did observe significant heterogeneity in the COVID-19-related death rate and ITU admission between different studies (χ 2 = 68.98; Second, although a higher rate of COVID-19-related deaths was observed among HCT recipients in the setting of active GvHD, the information available for this subgroup of HCT recipients was insufficiently detailed to make any meaningful observation on whether this reflects those with acute versus chronic GvHD.
Third, we found evidence of duplicate publication bias. For example, we identified one study [7] involving Center for International Blood and Marrow Transplant Research data where some patient data may have been published separately as single-centre experiences [6,35], while another study [8] utilising EBMT registry data may have included data that were reported separately in other studies. Such 'double reporting' could potentially amplify the contribution of certain cases in determining the characteristics of the overall study population and therefore distort its true profile. In addition, limitations in resources and COVID-19 testing capability during the initial stages of the pandemic are likely to have introduced selection bias towards symptomatic or hospitalised patients.
Fourth, due to variation in reporting across the selected studies, insufficient pooled data were available to meaningfully assess potential risk factors for adverse COVID-19 outcomes such as comorbidity and performance status. However, we did identify five studies [7,8,28,30,38] that reported comorbidities and/or baseline fitness levels of HCT recipients and their correlation with COVID-19-related death rates. Despite consistencies in methods used to assess these risk factors, the presence of comorbidities [28,30,38] [29,[47][48][49][50]. In fact, the COVID-19-related death rate observed in our study of HCT recipients is similar to that of unselected patients hospitalised with COVID-19 during the same time period (February-April 2020) [51,52].
In summary, this meta-analysis describes COVID-19 outcomes in 36 studies involving 2141 HCT recipients across the globe. We found the COVID-19-related death rate to be 21%-lower than that of unselected patients with HM and similar to that of patients hospitalised with COVID-19 in the general population during the same time period.
COVID-19-related deaths were increased among HCT recipients who developed COVID-19 within 1 year of HCT, within 6 months of receiving treatment with immunosuppressants, or in the context of active GvHD. These novel observations support the idea that HCT should remain an integral part of HM treatment protocols during the COVID-19 pandemic. However, HCT recipients who are at increased risk of COVID-19-related death should be prioritised for surveillance and preventative measures.

FUNDING INFORMATION
No funding was received for this meta-analysis.

DATA AVAILABILITY STATEMENT
The extracted data are available upon request from the corresponding author.

PATIENT CONSENT STATEMENT
Not applicable.