Patients with chronic medical conditions (sickle cell anemia of any severity, Types I & II diabetes, congestive heart failure, myocardial infarction, arthritis, chronic lung problems, gastrointestinal disorders, back problems and angina) have worse physical role and social functioning, mental health, health perception, and/or body pain compared with patients with no chronic conditions [2, 15, 16]. Moreover, pain, by itself, has a negative impact on the financial, emotional, legal, familial, physical, social, occupational and behavioral dimensions of life . Alleviation of pain by different modalities has been shown to improve the QOL for conditions other than sickle cell disease [17–20].
Hallmarks of SS include both recurrent episodes of acute pain as well as chronic pain. Woods et al  used the SF-36 to measure eight domains of health related to QOL in 143 adult SCD patients. Compared with patients with other chronic conditions, patients with SCD had lower (worse) scores than all other groups in the domains of physical role functioning, social functioning, health perception and body pain. In the domain of physical functioning, they had very low scores comparable to the scores of patients with congestive heart failure. Health and functional status scores for patients with SCD were similar to or lower than scores for patients with diabetes, congestive heart failure or back problems [[2, 15–17] Table 1].
The impact of SCD on QOL is apparent in socioeconomic data on 3,538 African-American patients enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD). That study found that a higher percentage of patients were unemployed and disabled compared to the US African-American population . Fuggle et al  found that sickle cell pain resulted in over seven times increased risk of absenteeism from school and was highly disruptive of social and recreational activity of children with SCD. However, Kater et al , found that children with SCD in the Amsterdam area were compromised in the physical and psychological well-being, but not in cognitive or social aspects of QOL. Anie et al  reported that recurrent pain is not the only feature of SCD but other impairments in health-related quality of life are also important features. McClish et al  found that patients with SCD experience health-related quality of life that is worse than in the general population and most similar to patients undergoing hemodialysis. These studies [22–24], however, were not randomized, double-blind clinical trials, which MSH was.
Treatment of SS patients with HU improves their clinical and hematological characteristics [8, 9, 23, 24]. The present data show that hydroxyurea can also improve some measures of QOL including "general health now," general health perception and pain recall. The effect was especially evident in patients with sustained HbF response to HU. The strength of the favorable effect on social functioning, however, was not significant (p > 0.01).
Lack of demonstrable effect of HU relative to PL on certain QOL measures in our patients (physical functioning, physical role and ladder of life) may be the result of issues inherent in the process of selection for the MSH of patients with moderate-to-severe disease who were already debilitated and had irreversible effects of their disease. Our patients had frequent acute pain episodes and high levels of mean pain scores reported at baseline (Fig. 1A and 1B). Even though many experienced an average of 50% reduction in acute pain episodes [8, 9], they still had frequent acute pain episodes and high levels of chronic pain. Patients with complications like avascular necrosis may have irreversible limited range of motion of affected joints and patients with previous strokes may have permanent neurological defects. In our study there was strong evidence that these aspects of quality of life were influenced by the patients' quality of life, daily pain, and annual crises rate before enrollment (Table 2). Earlier treatment of individuals with SS before they have severe consequences of their disease may be an area for future investigation.
The absolute scores by the ladder of life scale are better than expected. This may reflect the optimism and positive attitudes of subjects who enrolled in this clinical trial. Subjects who consented to participate in the study may have been eager to benefit from the possibility of improvement that could be brought in by HU therapy; they received regular attention and clinical center staff support that may not be available to all patients with SCA.
Even though the high and low HbF responder analysis is post-hoc (i.e., based on 2-year HbF data after the QOL data was collected), the HbF responses occurs within weeks of HU initiation and is sustained through 2 years of treatment. Our data indicate that the increase in HbF level in subjects with SCD reduces the frequency of painful episodes [8, 9] and now is shown to improve certain measures of HQOL. Because subjects in this study already had moderate-to-severe SS, improvements in QOL with HU treatment relative to PL were moderate and concentrated among those patients with high HbF response to HU. A question for further investigation is whether patients with less severe disease, treated with HU before they develop irreversible debilitating side effects, may benefit from prevention of loss of health status and quality of life.