key: cord-0909787-2179dzzv
authors: Amonoo, Hermioni L.; Topping, Carlisle EW; Clay, Madison A.; Reynolds, Matthew J.; Rice, Julia; Harnedy, Lauren E.; Longley, Regina M.; LeBlanc, Thomas W.; Greer, Joseph A.; Chen, Yi-Bin; DeFilipp, Zachariah; Lee, Stephanie J.; Temel, Jennifer S.; El-Jawahri, Areej
title: Distress in a Pandemic - The Association of the Coronavirus Disease-2019 (COVID-19) Pandemic with Distress and Quality of Life in Hematopoietic Stem Cell Transplantation (HSCT)
date: 2021-09-15
journal: Transplant Cell Ther
DOI: 10.1016/j.jtct.2021.09.001
sha: 0598bb6b22300f2730a057195303c73726d0b549
doc_id: 909787
cord_uid: 2179dzzv

BACKGROUND: The global coronavirus disease 2019 (COVID-19) pandemic has drastically disrupted cancer care, potentially exacerbating patients’ distress levels. Patients undergoing HSCT may be especially vulnerable to this pandemic stress. However, the associations of the COVID-19 pandemic with distress, fatigue, and QOL are not well understood in this population. METHOD: In a cross-sectional analysis of data from 205 patients undergoing HSCT enrolled in a supportive care trial, we compared baseline pre-HSCT distress (depression, anxiety, and posttraumatic stress disorder [PTSD]) symptoms, fatigue, and QOL between enrollees pre- (i.e., 03/2019-01/2020) and during (i.e., 03/2020-01/2021) the COVID-19 pandemic. We used linear regression models adjusting for sociodemographics and cancer diagnosis to examine the associations between enrollment period and patient-reported outcomes. We used semi-structured qualitative interviews in 20 allogeneic HSCT recipients who were ≥3-months post-HSCT to understand the impact of the COVID-19 pandemic on their recovery post-HSCT. RESULTS: Prior to COVID-19, 124 participants enrolled, while 81 participants enrolled during the pandemic. The cohorts had similar baseline demographics and disease risk factors. In multivariate regression models, enrollment during COVID-19 was not associated with pre-HSCT symptoms of depression, anxiety, PTSD, fatigue, or QOL impairment. COVID-19-era participants reported themes of negative (e.g., increased isolation) and positive (e.g., engagement with meaningful activities) implications of the pandemic on HSCT recovery. CONCLUSIONS: We found no differences in pre-HSCT distress, fatigue or QOL in patients undergoing HSCT prior to or during the COVID-19 pandemic. Patients in early recovery post-HSCT, however, report both negative and positive implications of the COVID-19 pandemic on their lives.

The global coronavirus disease-2019 (COVID-19) pandemic has drastically disrupted many aspects of life and healthcare in unparalleled ways. For patients with cancer, it has impacted both treatment and recovery trajectories. 1, 2 Patients with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT) are especially vulnerable to care changes imposed by the pandemic due to factors associated with HSCT, including the intensive treatment with a prolonged hospitalization, high burden of physical symptoms due to potential toxic side effects, and quality of life (QOL) challenges in recovery. [3] [4] [5] [6] Outside the hospital, HSCT patients grapple with weeks of social isolation and quarantine requirements from a compromised immune system, contributing to distress and QOL impairments in this population.

While a few studies have described the implications of the COVID-19 pandemic for HSCT recipients, previous research has focused on the pandemic's impact on HSCT logistics and COVID-19 complications. [7] [8] [9] However, the associations of the COVID-19 pandemic with patientreported distress, fatigue, and QOL are not well understood.

Compared to other cancer populations, many HSCT recipients travel longer distances for their care and require increased caregiver and social support network involvement to ensure successful acute follow-up care (e.g., bi-weekly clinic visits, medication management) and recovery. 10 Additionally, HSCT recipients frequently depend on their caregivers for basic activities of daily living (e.g., meal preparation, household cleaning) to reduce risk of infections while their immune system recovers. 11 Hence, pandemic restrictions on lifestyle and travel may have negatively impacted the size and effectiveness of social support networks for HSCT recipients, intensifying their distress. 12 Despite the widespread notion that the COVID-19 pandemic has exacerbated distress symptoms in patients with cancer, 13 data are limited for patients with hematologic malignancies undergoing HSCT who have well-documented heightened psychological distress, fatigue, and impaired QOL irrespective of a pandemic. 14 Accordingly, we aimed to assess the association of the COVID-19 pandemic with distress, fatigue, and QOL in the HSCT population quantitativelly and qualitatively. We hypothesized that the COVID-19 pandemic would be associated with increased distress and fatigue, and decreased QOL.

We conducted a cross-sectional analysis of data from 205 patients with hematologic malignancies undergoing HSCT enrolled in an ongoing multi-site, randomized supportive care trial at Massachusetts General Hospital, Boston, MA; Duke University Medical Center, Durham, NC; and Fred Hutchinson Cancer Research Center, Seattle, WA (NCT03641378). We compared baseline pre-HSCT symptoms of distress (depression, anxiety, and posttraumatic stress disorder [PTSD]), fatigue, and QOL between participants enrolled pre-COVID-19 (i.e., 03/2019-01/2020) and participants enrolled during the COVID-19 pandemic (03/2020-01/2021).

The study was approved by the Institutional Review Boards at all participating sites. All participants provided written informed consent.

Two hundred five of 347 (59%) eligible participants enrolled in the study. Participants were adults (≥ 18 years old) with hematologic malignancy hospitalized to receive autologous or allogeneic HSCT. Patients who could read and respond to questionnaires in English, Spanish, or with an interpreter were eligible to participate. We excluded patients undergoing HSCT for benign hematologic conditions, those undergoing outpatient HSCT, and those with major psychiatric or cognitive conditions prohibiting their adherence to study procedures, as determined by their treating oncologist.

At enrollment, we collected participants' sociodemographics-age, gender, race, ethnicity, education, religion, income, living situation, and relationship status. We used the electronic health record (EHR) to collect disease, clinical, and treatment-specific information.

We assessed distress (depression and anxiety symptoms) using the Hospital Anxiety and Depression Scale (HADS), 15 a 14-item questionnaire containing two seven-item subscales assessing depression (HADS-D) and anxiety (HADS-A) symptoms during the past week (score range: 0-21). 15 Higher scores on the HADS-D or HADS-A subscale is indicative of higher levels of depression or anxiety symptoms, respectively. PTSD symptoms were assessed using the 17item PTSD Checklist-Civilian Version (PCL). The PTSD symptom severity score was obtained by summing the scores from each of the 17 items, with higher scores indicating worse PTSD symptoms (score range: 17-85). 16, 17 Fatigue was measured with the 13-item Functional Assessment of Cancer Therapy-Fatigue (FACT-F) subscale (score range: 0-52). 18 Higher scores on the FACT-F subscale indicate lower levels of fatigue. 18 We assessed QOL using the 47-item Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) which has five subscales that assess physical, functional, emotional, and social well-being, as well as bone marrow transplant-specific problems (score range: 0-196). 19 A five-point difference in the FACT-BMT score is considered clinically significant; higher scores indicate better QOL. 19, 20 

We performed all statistical analyses with STATA 16.0 (StataCorp, College Station, TX). We considered a two-sided p-value <0.05 to be statistically significant. Participants' baseline characteristics were summarized using descriptive statistics (e.g., mean, standard deviation) for continuous variables and proportions for categorical variables. We used two sample t-tests and linear regression models to compare baseline pre-HSCT distress (depression, anxiety, PTSD symptoms), fatigue, and QOL between participants enrolled prior to or during the COVID-19 pandemic. We used multivariate regression models to examine the associations of the period of enrollment with patient-reported distress, fatigue, and QOL, while adjusting for age, gender, race, relationship status, education, transplantation type, and underlying diagnosis. We did not adjust for randomization as the outcome variables were collected at baseline prior to randomization.

To further understand HSCT recipients' experiences during the COVID-19 pandemic, we For analysis, we utilized directed content analysis, a widely used qualitative approach for examining the breadth and scope of patient experiences, and extracted themes from the data using an established framework from pre-existing literature. 21, 22 Participant responses were independently coded verbatim without any interpretations by two study team members (HA and LH) to avoid bias. We used complete sentences as the coding unit. Codes were informed by both interview question and qualitative interview data. We modified the coding structure after reading a small number of transcripts several times to test the codes. We discussed emerging themes from the codes and adjudicated discrepancies while reviewing interview transcripts to ensure that the themes reflected the original data. In addition to deriving core interview themes, we resolved discrepancies using transcript review, discussion, and consensus. With a sample size of 20 participants and a narrow focus, thematic saturation was achieved. Table 1 summarizes participants' baseline characteristics. While 60.5% (n=124) of participants were enrolled pre-COVID-19 pandemic, 39.5% (n=81) enrolled during the pandemic. Baseline characteristics between the groups were similar. The majority of participants identified as non-Hispanic (n=185; 90.2%), White (n=150; 73.2%), female (n=131; 63.9%), and married (151; 73.6%) with a mean (SD) age of 54.9 (11.7) years. Participants had diagnoses of leukemia (n=67; 32.7%), multiple myeloma (n=58; 28.3%), lymphoma (n=48; 23.4%), or myeloproliferative neoplasms (n=32; 15.6%). Table 2 summarizes the unadjusted comparison of baseline pre-HSCT patient reported outcomes between our two groups. Depression, anxiety, PTSD symptoms, QOL, and fatigue were not different beween participants enrolled pre-COVID-19 versus those enrolled during the COVID-19 pandemic.

In multivariate adjusted regressing models, enrollment during COVID-19 was not associated with pre-HSCT symptoms of depression (B=0.004; 95% CI, -0.018 to 0.025; p=0.733), anxiety (B=0.008; 95% CI, -0.012 to 0.027; p=0.443), PTSD (B=0.004; 95% CI, -0.004 to 0.012; p=0.348), fatigue (B=-0.001; 95% CI, -0.008 to 0.005; p=0.732) or QOL (B=-0.001; 95% CI, -0.005 to 0.003; p=0.570) ( Table 3) .

Our qualitative analysis of data from patients in post-HSCT recovery revealed that the COVID-19 pandemic had both negative and positive implications for patients' HSCT and recovery trajectories ( Table 4 ). Themes of negative implications of the pandemic highlighted by participants include a) increased isolation during HSCT hospitalization in the setting of restricted visitor policies, b) increased isolation at home due to states' restrictions of social gatherings and global restrictions on travel, and c) increased perceived distress on caregivers as they worried about transmitting SARS-CoV-2 to the patient. Participants expressed the following themes of positive implications of the pandemic: a) increased availability of social support as several family members were working or schooling from home, b) as the COVID-19 pandemic has made precautionary behaviors commonplace, it was easier to enforce precautionary behaviors (e.g., masking, handwashing) among family and caregivers during the pandemic compared to prior to the pandemic, and c) decreased stigma of precautionary behaviors (e.g., masking) as everyone was required to adhere to statewide and nationwide precautionary behaviors.

In this study, we assessed the associations of enrollment during the COVID-19 pandemic with baseline pre-HSCT distress, fatigue, and QOL, in 205 patients undergoing HSCT in different geographic regions in the United States. Contrary to the widespread notion and our hypothesis that the COVID-19 pandemic has exacerbated symptoms of distress and fatigue, and worsened QOL in HSCT patients, we found no differences between pre-HSCT distress, fatigue, or QOL in our sample prior to or during the COVID-19 pandemic. However, from our qualitative assessment of HSCT recipients' experiences during the COVID-19 pandemic, we found that the pandemic has had both negative and positive implications on participant experiences following HSCT.

Our findings suggest that although the COVID-19 pandemic has altered many aspects and logistics of HSCT and recovery, 9, 12 it has not worsened pre-HSCT distress, fatigue, or QOL compared to before the pandemic. Indeed, well established factors such as patients' illness experience, treatment burden, uncertainty regarding future health and potential HSCT complications are still likely the driving force behind distress, fatigue, and QOL challenges in this population. [3] [4] [5] [6] Our study's focus on baseline pre-HSCT assessments likely captured the true contribution of the COVID-19 pandemic on patient-reported outcomes, accounting for any distress accompanying the HSCT itself. While peri-transplant patient-reported outcome screening is limited in the HSCT population, 23 screening during this phase of the care cycle may help identify patients at increased risk for distress, fatigue, and QOL challenges that are likely compounded by the treatment itself.

Another potential explanation for the discordance between our findings and the widespread notion of intensified patient distress reported by cancer clinicians is that the COVID-19 pandemic forced the whole world to live like HSCT recipients which may have put them at a more psychological advantage to managing pandemic related restrictions on life. 24 For example, HSCT recipients were already used to precautionary behaviors (e.g., wearing face masks in public) and limited interactions with large crowds. While our findings suggest that the COVID-19 pandemic was not associated with increased pre-HSCT distress, fatigue, and decreased QOL, it is possible that we are missing some longitudinal changes in distress given restrictions on visitors during the HSCT hospitalization. Our qualitative findings revealed that the pandemic has indeed had both negative and positive implications for HSCT recipients during their recovery. It is also possible that existing self-report measures that assess distress, fatigue, or QOL in cancer populations, do not capture pandemic-specific or COVID-19-specific stressors which are likely existential in naturepatients spontaneously reported that the ongoing COVID-19 pandemic has increased their thoughts and distress about mortality, something not typically elucidated by standard distress screening instruments in cancer populations.

Social support and caregivers play a critical role in the treatment and successful recovery of HSCT recipients. 11 Regardless of a global pandemic that imposes restrictions on travel and social interactions, social isolation during HSCT hospitalization and acute recovery is substantial and contributes significantly to distress that already accompanies the toxic side effects of HSCT.

It was, therefore, not surprising that a constant theme in our qualitative findings pertained to the pandemic's impact on social isolation and changes in the nature and structure of social support.

Some participants reported that the pandemic improved access to social support, while others reported that the pandemic has been a barrier to needed social support. Further, participants mentioned that the COVID-19 pandemic has increased distress symptoms in their caregivers, This study has several limitations. First, the majority of our study participants were non-Hispanic White, married, and educated, all of which may limit the generalizability of our findings, particularly given the disproportionate impact that the COVID-19 pandemic has had on ethnic minorities and underserved communities. 25 Second, the cross-sectional nature of our analyses limits our ability to comment on causality of our examined variables. Additional longitudinal assessments of patient-reported outcomes in the setting of a pandemic may be useful in obtaining a comprehensive understanding of the impact of the pandemic on this population. Third, while we were able to capture important aspects of distress through widely used selfreport measures for the HSCT population, it is likely that we were unable to capture the existential components of distress (e.g., increased thoughts about mortality reported qualitatively), 26 which may have been heightened by the pandemic. Fourth, while disease status appeared similar between the two groups, the post-COVID-19 cohort reflect a 35% drop in patients from the pre-COVID-19 cohort and patients who proceed to HSCT during a pandemic may be fundamentally different than those who were transplanted before the COVID-19 pandemic, both in terms of their disease and psychological status. Fifth, although our sample size is comparable to studies assessing patient-reported outcomes in this population, our null findings may simply be due to limited power to detect differences in patient-reported outcomes.

Sixth, while our study focused only on patients, including direct caregivers' perspectives from qualitative interviews would provide a more holistic view of the impact of the COVID-19 pandemic on patients' care experiences and social support. Finally, on average, patients are already quite distressed before undergoing HSCT compared to other medical procedures, and a pandemic may not increase it further.

In conclusion, we did not detect that the COVID-19 pandemic significantly worsened distress, fatigue, and QOL of patients about to undergo HSCT. However, we highlight the need to comprehensively explore the many factors (e.g., illness experience, treatment burden) that influence patient-reported outcomes in HSCT patients irrespective of the COVID-19 pandemic.

Our findings also underscore the importance of social support in HSCT recovery, especially during global pandemics which further imposes barriers and restrictions on social support networks for vulnerable cancer populations such as HSCT recipients.

This work was supported by the National Cancer Institute through grant K08CA251654 (to Dr. Amonoo). Dr. El-Jawahri is a scholar in clinical research for the Leukemia & Lymphoma Society.

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data. All were involved in drafting the article or revising it critically for important intellectual content. All provided final approval of the manuscript and agree to be accountable for all aspects of the work.

Health/BCG Digital Ventures and Blue Note Therapeutics. TWL reports the following disclosures from the past 24 months: personal fees for consulting or advisory boards from AbbVie, Agios, AstraZeneca, Amgen, Astellas, CareVive, BMS/Celgene, Daiichi-Sankyo, Heron, Flatiron, Otsuka, Pfizer, and Seattle Genetics; royalties from UpToDate; speakers bureau fees from Agios, AbbVie, and BMS/Celgene; grants and/or research contracts from the American Cancer Society, AstraZeneca, BMS, Jazz Pharmaceuticals, the NINR / NIH, and Seattle Genetics. SJL sits on a steering committee of Incyte and receives research funding from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, Takeda. The authors have no conflicts to report. With state and national mandates for infection control via precautionary behaviors (e.g., masking) in the United States, HSCT recipients reported less challenges and stigma in enforcing these required behaviors for their recovery "Well, maybe it's better that COVID's going on because other people are wearing a mask and you're more protected." (ID 4) "Fortunately, people have been more hygienically focused during the period, so people are wearing masks. This makes it convenient for myself." (ID 8) Increased availability of family and social support.

As the COVID-19 pandemic forced most work-places and educational institutions to go virtual and remote, participants reported increased availability of family and social support networks.

"I would say it made things easier for me and for my family because everybody is in a kind of lockdown or quarantine. ... So yeah, I think it had a positive effect. And also with some of my kids who were away in school at universities, they came back home and they continued studying from home online…I mean, having my kids around was really wonderful." (ID 11) Negative

Increased isolation Participants reported that "… So it was really hard. When I "Well, I'm confined. I'm just isolated…I think being confined is the worst. I can't even imagine somebody having nobody to be with when you're so confined." (ID 10) "The bottom line is, COVID has created more isolation and less support…Not knowing what's going to happen. I mean, I'm six months and I'm sitting here isolated in my house because of COVID." (ID 4) "Before anyone visits, it's always a concern whether they've had any sort of contact with anyone with COVID, and it's limited the amount of people I've been able to see during my 100 days, of initial recovery. And, going onward, it's again restricted the number of people I've been able to visit and interact with in person" (ID 8) Heightened patients' distress about being infected by SARS-CoV-2 and overall increased thoughts about mortality Participants articulated heightened distress (e.g., anxiety, fear) specifically pertaining to the COVID-19 pandemic with increased thoughts about COVID-related mortality if they were to contract the coronavirus.

"And I'm afraid to--if I have to do anything, I'm gloved and masked and I get worried about going to the hospital now for my blood transfusions and my doctor's appointments because of the COVID all over the place…. If COVID kills me after all I've been through, I will be totally pissed. Just want to let you know." (ID 10) "Well, yeah. I mean, I'm super anxious. I don't want to get sick. I don't want to get sick with COVID. And considering that I just had a stem cell transplant, I know I'm more vulnerable than others. So that's one of my biggest fears." (ID 17) "And I'd say also during the earlier hospitalization, I was very nervous about the nurses and the nursing assistants and everybody was coming close to me all the time and thinking, "Well, I don't know who they've been with and I don't know what people they live with, who are they seeing." And the spread of that got me a little bit nervous." (ID 12) Increased family and caregiver distress and burden Participants reported increased perceived distress on caregivers as they worried about transmitting COVID-19 to the patient "And it's also affecting my family, because they're limited as to what they could do, so I know that's been tough on them, too." (ID 17)

"So COVID has complicated things in my family, there's a lot of extra stress. My wife is a preschool teacher. She works with 12 young kids that the whole risk and fear of COVID, infecting her and therefore possibly infecting me is a significant stress for her all the time because I'm immuocompromised… And and it continues today where she's constantly worried about my health because of COVID." (ID 20) Caregiver role in care The restrictions of the COVID-19 pandemic resulted in some restrictions on family/caregiver involvement with inhospital care.

"Well, before COVID, my entire family would walk into that office, and every one of my children….

So when COVID hit, I then could still have them on the line virtually. I kind of still record the conversations, but it did make it harder on me so that I didn't have my support team around me to help figure out what was going on and next steps and--in the beginning first few months, there were a lot of questions." (ID 15) 

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