The relationship between frequency and severity of vaso-occlusive crises and health-related quality of life and work productivity in adults with sickle cell disease

Sickle cell disease (SCD) is a hemoglobinopathy that causes red blood cells to lose their oxygen carrying capacity and is associated with severe, systemic vascular complications. It is estimated that approximately 100,000 Americans have SCD [1]. Patients with SCD experience chronic pain, cardiovascular events, ulcers, fatigue, organ damage, and sickle cell-related pain crises, also referred to as vaso-occlusive crises (VOCs). Treatments used to manage symptoms or reduce complications of SCD include hydroxyurea, l-glutamine, and blood transfusions [2]; currently, the only available cure for SCD is bone marrow transplant [3].

Previous research has provided insight into many of the ways in which patients are impacted by SCD [4]. For example, patients with SCD report experiencing sleep disturbances [5], as well as deficits in both physical and mental well-being [6]. The extensive burden of SCD may also lead to an inability to maintain consistent work or schooling, engage in daily, social, or recreational activities, and participate in family life [7‐10]. In addition to the burden of SCD, the experience of VOCs also has detrimental impacts on the lives of patients, though these impacts have been less comprehensively studied. VOCs are caused by multi-cell adhesion or cell clusters that block or reduce blood flow, and are a substantial cause of morbidity in patients with SCD; severe crises have also been associated with increased mortality [11]. These events are unpredictable and can cause disruption and hardship in the lives of patients, sometimes requiring medical attention in emergency departments or sickle cell urgent care centers, or leading to inpatient hospitalization [12]. Previous occurrence of VOCs has been linked to deficits in domains of health-related quality of life (HRQoL) such as general health, vitality, and bodily pain [6].

SCD is associated with high healthcare resource utilization (HCRU), with VOCs being the most common cause of hospital and emergency department visits among patients with SCD [13]. High rates of HCRU have been linked to a variety of poor outcomes among patients with SCD, including lower HRQoL and likelihood of unemployment [14‐17]. Despite high HCRU, especially for acute treatment of VOCs [18], the type of care patients with SCD receive may nevertheless be suboptimal. Receiving adequate treatment is a challenge commonly faced by patients with SCD, particularly for those who are transitioning from pediatric to adult care. Patients may have difficulty finding experienced practitioners to treat their SCD, coordinating communication between providers in a multi-disciplinary care setting, and obtaining or maintaining adequate insurance coverage, all of which could in turn result in over-reliance on emergency departments for treatment [19]. Perhaps unsurprisingly, patients themselves indicate that they prefer treatments they can administer at home [20], and report managing most of their VOCs at home [21]. Research has suggested that patients who prefer treating their pain at home believe that going to a hospital is not in their best interest and feel that they are responsible for managing their pain [22].

Given the seriousness of VOCs, there is an on-going need to better understand the ways in which these events impact patients with SCD. Although patients themselves have identified VOCs as one of the most debilitating aspects of their disease [20], minimal research has been conducted to quantify the extent of their impact on patients’ lives. Therefore, additional research into their effect on patients’ HRQoL and other outcomes is needed to provide insight into areas of unmet need and guide treatment development. Recognizing these gaps in the literature, the goal of this study was to examine the relationship between the frequency and severity of VOCs and HRQoL and work productivity impairment, using patient-reported data.

The goal of this study was to explore the disease experience of patients with SCD, focusing primarily on better understanding the ways in which patients are impacted by the frequency and severity of VOCs. To our knowledge, this is one of the few studies designed to comprehensively investigate the impacts of both SCD and VOCs on multiple dimensions of patients’ lives. Data obtained from the cross-sectional online survey of adults with SCD provided evidence to demonstrate that patients experience impacts of SCD across many different aspects of their lives, including employment, education, and personal relationships. In addition, the frequency and severity of VOCs were associated with impacts on HRQoL and work productivity.

The frequency and severity of VOCs were related to multiple domains of HRQoL. In particular, patients with more frequent (or severe) VOCs reported greater impacts on areas known to be affected by SCD, as measured by the ASCQ-Me, than patients with less frequent (or severe) VOCs. Moreover, these patients experienced deficits in areas of emotional functioning, social functioning, and stiffness that were meaningfully lower than a benchmark SCD population. These findings extend past research that has linked the previous occurrence of VOCs to lower scores on general health, vitality, and bodily pain domains (as measured by the SF-36® Health Survey) [6] by demonstrating that HRQoL is impacted not only by any past experience of VOCs, but also by the frequency and severity of these experiences. The findings of the current study also highlight impacts that extend beyond physical functioning, illustrating the effects of VOCs on social and emotional functioning as well.

In addition to impacts on HRQoL, results demonstrate that the frequency of VOCs is associated with specific aspects of work productivity. The number of VOCs over a 12-month period was related to the amount of missed worktime in the 7 days preceding survey administration, suggesting that the impacts of VOCs on patients’ lives may extend beyond the end of the event itself. To the best of our knowledge, the WPAI has not been administered to patients with SCD in an observational setting. As such, the results obtained from this study cannot be compared to, or interpreted, in light of previous findings. However, findings can be compared to those reported in different disease areas, helping to better contextualize the current results. Specifically, the quantity of absenteeism reported by patients with the most frequent or severe VOCs is nearly double what has been reported by patients with non-malignant chronic pain (19.4%) [29], and by patients who have recently completed treatment for breast cancer (21–25%) [30], but slightly less than the absenteeism reported by patients who currently have breast cancer (56–61%) [30]. Absenteeism is calculated as the number of work hours missed, divided by the total number of hours a patient could have worked. Thus, an absenteeism score of 34.99 (the average score of patients with the most frequent VOCs) is generally equivalent to missing 14 h of a 40-h work week, while an absenteeism score of 39.59 (the average score of patients with the most severe VOCs) is generally equivalent to missing 16 h of a 40-h week. Put this way, the impacts of VOCs can be described more concretely, elucidating the ways in which employed patients with frequent or severe VOCs are impacted by SCD.

Given the degree of work impairment experienced by patients with SCD, and in particular by those with more frequent or severe VOCs, it is unsurprising that many patients also reported experiencing negative impacts on their overall employment status. Previous qualitative work has reported that patients with SCD find it difficult to manage their jobs. For example, the FDA’s Voice of the Patient report describes that patients with SCD experience difficulty keeping up with their work due to both absences from work and stress caused by various aspects of the disease [20]. Other qualitative research has documented patients’ descriptions of challenges related to finding and maintaining adequate employment; patients discussed difficulty keeping jobs or building job history, and having to leave jobs that were too physically demanding [10]. Our results extend these findings by helping to quantify the frequency with which patients experience such impacts, showing that such experiences are relatively widespread among patients with SCD. Similar to the impacts on employment, patients in our study also reported that their SCD had impacted their personal relationships and negatively impacted their education. Overall, the number of patients who experienced negative impacts on education was fewer than those who experienced negative impacts on employment. Patients with SCD often experience a difficult transition from pediatric to adult care [31], and may struggle to obtain consistent and effective care as young adults, thus potentially increasing the likelihood that SCD will negatively affect various facets of their adult lives. Indeed, approximately 75% of the patients in this study reported experiencing barriers to receiving care for their SCD, such as difficulty affording healthcare services, limited health insurance, discrimination by healthcare professionals, difficulty trusting healthcare professionals, and a lack of specialized treatment centers. Increasing access, options, and quality of SCD-related care may improve patients’ employment-related outcomes.

This study had some limitations. As with any information collected through patient report, recall bias could affect reports of events. Second, diagnosis of SCD was entirely self-reported. While recruitment of patients through collaboration with SCD-related organizations and advocacy groups in the absence of explicit physician confirmation has been reported elsewhere [32, 33], the trade-offs between relying on self-report (e.g., more expedient data collection, ability to recruit across a broad geographic region) and obtaining additional confirmation must be considered. Third, selection bias could affect the type of patients who participated in the survey; the survey could only be completed by individuals with internet access, and those who are unfamiliar or less comfortable using this type of technology may have been less likely to participate. Fourth, the study was designed to be cross-sectional, exploratory, and largely descriptive. As such, none of the relationships reported here can be interpreted as causal, nor can longitudinal relationships be inferred. However, the results of the study are informative in their own right and can provide a solid foundation for additional future research.

Balancing the aforementioned limitations, this study also had several particular strengths. First, the study sample was quite large, particularly for a rare disease. Second, evaluation of the study sample strongly suggests that it is generally representative of the larger SCD patient population. While more women than men completed the survey, scores obtained on the ASCQ-Me were nearly identical to those from an SCD benchmark population [23], and the distribution of patients across race, types of SCD, and across US geographic regions is similar to what has been reported in previous studies [34]. Third, the survey assessed a variety of different concepts related to the experience of patients with SCD, including both validated patient-reported outcome measures and items written specifically for this study. This approach allowed for a clearer assessment of the ways in which patients are impacted by the disease. For example, only relying on the WPAI to measure work-related outcomes would capture the experiences only of patients who were currently employed, failing to take into consideration the perspectives of unemployed patients, who comprised 61% of the total study sample. Rather, the WPAI was fielded in conjunction with a series of items regarding the lifetime experiences of all patients, regardless of current employment status, thus providing a more complete understanding of this particular outcome.

This study provides evidence to demonstrate a link between patient outcomes such as HRQoL and work impairment, and the frequency and severity of VOCs. The findings presented in this study provide a solid foundation for future research, which should aim to investigate a causal relationship between these factors. Additional research should also explore how health interventions or the alleviation of structural or environmental barriers to receiving healthcare may improve HRQoL and employment opportunities among patients with SCD.

In conclusion, this study provides a comprehensive description of the patient experience with SCD, with a specific emphasis on highlighting the ways in which VOC frequency and severity impact patients’ HRQoL and work productivity. This research provides evidence to suggest that VOCs may have broad and cumulative impact on aspects of life such as emotional and social functioning which may last beyond the end of the event itself.