Longitudinal assessment of fatigue and health-related quality of life in adults with immune thrombocytopenia in China

doi:10.21203/rs.3.rs-3020441/v1

Background

Currently, there are few studies focusing on fatigue and health-related quality of life (HRQoL) longitudinally among immune thrombocytopenia (ITP) adults, especially in China. We aimed to evaluate changes in fatigue and HRQoL and identify the associated factors from admission to three months after discharge in Chinese adult ITP patients.

Methods

Patients’ characteristics, and the self-reported answers of the Functional Assessment of Chronic Illness Therapy (FACIT-F) and the ITP-specific Patient Assessment Questionnaire (ITP-PAQ) at admission (T0), at discharge (T1), and three months after discharge (T2) were collected. Linear mixed effects models were used to examine overall changes over time and associated factors in FACIT-F and ITP-PAQ scores at T0, T1, T2.

Results

The data of 175 ITP adults were included. The mean score of FACIT-F at T0 was 37.2 and increased to 39.0 at T1, while then tended to decrease to the level of baseline at T2 (34.7). Patients who were single, retired, had persistent ITP, splenomegaly had more severe fatigue, whereas those who had not received any prior treatment and had a bleeding score of 0 at admission had milder fatigue. The mean score of ITP-PAQ was 57.7 at T0, then gradually increased to 60.3 at T1 and 62.8 at T2. Patients with persistent ITP and those who have never received treatment for ITP have better HRQoL.

Conclusion

Adult ITP patients in China have non-negligible impairment in fatigue and HRQoL. Patients' fatigue improved at discharge but worsened at three months after discharge, while HRQoL gradually improved over time.

Immune thrombocytopenia

HRQoL

FACIT-F

ITP-PAQ

longitudinal

Immune thrombocytopenia (ITP) is an autoimmune disease which is characterized by decreased platelet count (< 100×10⁹ / L). The annual incidence in adults is about 50–100 new cases per million population around the world, and it brought a high clinical and economic burden [1; 2]. The cause of the disease is insufficient platelet release from megakaryocytes in the bone marrow or accelerated platelet destruction [3]. According to the disease duration, it is classified into newly-diagnosed (0–3 months), persistent (3–12 months), and chronic (> 12 months) [4]. The symptoms range from no or only minor bleeding spots, ecchymosis to epistaxis, gingival bleeding, oral bleeding, menorrhagia, etc., while severe or life-threatening bleeding is rare [5]. Standard first-line therapies for patients with newly-diagnosed ITP include corticosteroids, intravenous immunoglobulin (IVIg), and anti-D immunoglobulin [6]. Second-line therapy in non-responders or relapsed patients may include thrombopoietin receptor agonist (TPO-RA), immunosuppressive agents such as rituximab, or splenectomy [4]. These treatments can significantly increase platelet counts and reduce bleeding symptoms in most patients, including some with severe refractory thrombocytopenia.

ITP persists and becomes chronic in most adult patients, and patients can live for a long time with ITP with the use of the treatments mentioned above. Meanwhile, frequent and costly hospitalization and treatment-induced adverse events in adults with ITP increase patients’ burden. So, health-related quality of life (HRQoL) is regarded as a disproportionate importance in ITP patients [5]. Studies conducted in America, Italy, and China, have consistently shown that adults with ITP had lower HRQoL than the general population [7–9]. Besides, fatigue is also a characteristic that cannot be ignored in ITP [10]. Although the cause of ITP-related fatigue was not fully understood, previous studies suggested that fatigue could be caused by the disease itself or by the side effects related to the treatments [10]. Fatigue can affect their daily life and have a further impact on the HRQoL. Studies in the United States and the United Kingdom have found that ITP patients experience fatigue in a higher proportion than the general population [11]. A previous study conducted in China has also found significantly more severe fatigue in ITP patients compared to the general population [12].

Due to the long-life expectancy of ITP, understanding and evaluating fatigue and HRQoL of ITP patients is important for evaluating strategies to improve clinical outcomes, thereby improving their overall health and well-being [5]. However, most studies were focused on HRQoL in patients receiving specific treatment or enrolled in clinical trials.[5] Besides, most published studies in China were cross-sectional or only focused on children with ITP [12; 13]. There is lacking evidence of longitudinal evaluation of fatigue and HRQoL in a real-world setting among Chinese adult patients with ITP.

The aim of this study was to assess changes in fatigue and HRQoL at admission, at discharge, and three months after discharge and identify their associated factors among Chinese adult patients with ITP.

This study was a prospective, single-center, cohort study evaluating fatigue and HRQoL among adult ITP patients hospitalized at the Institute of Hematology and Blood Disease Hospital (IHBDH), Tianjin, China. The study was approved by the ethics committee of the IHBDH, Tianjin, China (No. QTJC2022040-EC-1).

2.1 Study population

Patients who were hospitalized at the IHBDH from September 2020 to February 2021 were recruited in this study. IHBDH is the largest National-level scientific research professional medical institution for hematology, integrating medical treatment, scientific research, teaching, and industry [14]. Thrombus Hemostasis Diagnosis and Treatment Centre of IHBDH mainly admitted patients with hereditary and acquired hemorrhagic and thrombotic diseases, including ITP, from all over the country. The inclusion criteria were as follows: (1) aged ≥ 18 years old; (2) was diagnosed with ITP; (3) was hospitalized; (4) was clearly aware, with certain reading and comprehension skills; (5) voluntarily participated in this study; and (6) gave informed consent.

2.2 Data collection

Demographic (age, sex, marital status, and occupation status) and clinical data (disease phase, previous treatments, platelet level and bleeding symptoms at admission, comorbidities, length of stay, and treatments during the hospitalization) of the patients were obtained from the medical records stored in the intelligent data platform of the IHBDH. Previous treatments were divided into no-treatment, first-line, and second-line therapy. First-line therapy refers to oral corticosteroids and/or intravenous immunoglobulin (IVIg) [15]. Second-line therapy includes treatments other than steroids and IVIg. Treatments during the hospitalization were divided into no treatment, first-line therapy, rituximab, TPO receptor agonist, and other second-line treatment.

Patients were asked to complete the Functional Assessment of Chronic Illness Therapy (FACIT-F) and the ITP-specific Patient Assessment Questionnaire (ITP-PAQ) at baseline (the day at admission, T0), at discharge (T1), and three months after discharge (T2) by themselves. Patients completed the questionnaires for the first two time points in an office room at the hospital without being disturbed. Answers to the questionnaires for the third time point were collected through the online survey.

2.3 Measures

Fatigue measure. FACIT-F was used to assess the patients’ fatigue levels in the past week and their impact on cognition, physiology, psychology, and social interaction. FACIT-F was originally designed for cancer, but its reliability and validity were demonstrated in other chronic diseases, including ITP, and were widely used around the world [16–18]. This scale contains 13 items, and it uses the Likert 5-level scoring method in which 0 represents "not at all", 1 represents "a little bit", 2 represents "somewhat", 3 represents "quite a bit", and 4 represents "very much". Items An5 and An7 are scored forward (“An” is the alphanumeric code), while the remaining items are scored backward. The score of the entire scale is the sum of the scores of each item. The total score of the scale, which is the sum of the scores of each item, ranges from 0 to 52 points. The higher the score, the lighter the patient's fatigue [12].

HRQoL measure. HRQoL was assessed with the ITP-PAQ. The ITP-PAQ developed by Mathias et al. is the first ITP-specific questionnaire [19]. The ITP-PAQ includes 44 questions aggregated in 10 scales: symptoms (S), fatigue (Fat.), bother (B), activity (A), psychological (PH), fear (F), overall quality of life (OQoL), social activity (SA), work (W), women’s reproductive health (WRH) [20]. The response option uses a Likert-type scale from 4 to 7 points. The scoring is a summary scoring scale, and the weights of items in each scale are equal. The scale's scores range from 0 to 100, with higher scores indicating better HRQoL [20]. Amgen retains the right to this QoL scale [21].

Bleeding measure. The World Health Organization (WHO) bleeding scale was used to assess patients' bleeding symptoms at admission. The WHO bleeding scale is a simple five-point scale with 0 representing “no bleeding”, 1 representing “petechiae”, 2 representing “mild blood loss”, 3 representing “gross blood loss”, and 4 representing “debilitating blood loss” [22]. According to the score, patients can be divided into three mutually exclusive groups, i.e., no bleeding group (0 points), low-risk group (1–2 points), and high-risk group (> 2 points).

2.4 Data analysis

Descriptive statistics were reported as frequencies and percentages to describe categorical variables and the mean ± standard deviation (SD) to describe continuous variables. The FACIT-F and ITP-PAQ scores were summarized for the entire cohort at each time point (T0, T1, and T2) across different groups. Nonparametric Whitney-Mann-U tests or Kruskal-Wallis tests were used to compare the scores of FACIT-F and ITP-PAQ according to the number of groups compared. Linear mixed effects models were used to examine the relationships between changes in both scales and demographic, clinical, and treatment-related characteristics at baseline [23]. Patients who completed at least one FACIT-F and ITP-PAQ questionnaire at any time point were included in the mixed model analysis. The scores of FACIT-F and ITP-PAQ were included as the dependent variable in the model. Age, sex, marital status, occupation status, disease phase, previous treatment, platelet level at baseline, bleeding scores at admission, comorbidities, length of stay, treatments during the hospitalization, and a categorical variable indicating the time points (T0, T1, and T2) were included as the independent variables in the model.

All statistical tests were two-sided, and P < 0.05 was considered statistically significant. All statistical analyses were conducted using SPSS software version 26.0 (IBM Corporation, Armonk, New York, USA).

3.1 Demographic and clinical characteristics at baseline

A total of 175 patients with primary ITP were recruited at T0 in our study. One hundred and eleven (63.4%) patients completed the questionnaires at T1, and 51 (28.0%) completed them at T2.

The demographics and clinical characteristics of the patients at three time points are shown in Table 1. At baseline, female patients (N = 116) were about twice as likely as males (N = 59), and 145 (82.9%) patients were married. Among 175 patients, 39 (22.3%) were newly diagnosed, 40 (22.9%) were persistent, and 96 (54.9%) were chronic. Twenty-two (12.6%) patients were treatment-naïve, and 153 (87.4%) patients had received prior therapy (37 received first-line treatment, and 116 received second-line treatment). The admission platelet counts among 74 (42.3%) patients were < 10×10⁹/l, and the WHO bleeding score at admission among 118 (67.4%) patients was ≥ 1. One hundred and twenty-one (69.1%) patients had comorbidities.

Table 1

The demographics and baseline clinical information of patients with ITP
Characteristics, n (%)	T0	T1	T2
Total	175 (100)	111 (100)	51 (100)
Gender
Male	59 (33.7)	32 (28.8)	22 (43.1)
Female	116 (66.3)	79 (71.2)	29 (56.9)
Age (years)
18–29	30 (17.1)	20 (18)	10 (19.6)
30–39	33 (18.9)	19 (17.1)	15 (29.4)
40–49	42 (24)	31 (27.9)	10 (19.6)
50–59	37 (21.1)	16 (14.4)	10 (19.6)
≥ 60	33 (18.9)	25 (22.5)	6 (11.8)
Marital status
Single	30 (17.1)	21 (18.9)	11 (21.6)
Married	145 (82.9)	90 (81.1)	40 (78.4)
Occupation
Student	6 (3.4)	5 (4.5)	5 (9.8)
Employed	109 (62.3)	62 (55.9)	31 (60.8)
Retired	22 (12.6)	17 (15.3)	5 (9.8)
Unemployed	38 (21.7)	27 (24.3)	10 (19.6)
Phase
Newly diagnosed	39 (22.3)	21 (18.9)	12 (23.5)
Persist	40 (22.9)	31 (27.9)	12 (23.5)
Chronic	96 (54.9)	59 (53.2)	27 (52.9)
Previous treatment
No treatment	22 (12.6)	16 (14.4)	5 (9.8)
First-line	37 (21.1)	22 (19.8)	9 (17.6)
Second-line	116 (66.3)	73 (65.8)	37 (72.5)
Platelet level at admission(×10⁹/l)
<10	74 (42.3)	41 (36.9)	25 (49)
10–29	67 (38.3)	45 (40.5)	15 (29.4)
≥ 30	34 (19.4)	25 (22.5)	11 (21.6)
Bleeding scores at admission
0	57 (32.6)	34 (30.6)	18 (35.3)
1–2	65 (37.1)	41 (36.9)	16 (31.4)
>2	53 (30.3)	36 (32.4)	17 (33.3)
Number of other diseases
0	54 (30.9)	29 (26.1)	12 (23.5)
1–2	87 (49.7)	59 (53.2)	29 (56.9)
>2	34 (19.4)	23 (20.7)	10 (19.6)
Anemia
Yes	26 (14.9)	19 (17.1)	5 (9.8)
No	149 (85.1)	92 (82.9)	46 (90.2)
Splenomegaly
Yes	27 (15.4)	16 (14.4)	7 (13.7)
No	148 (84.6)	95 (85.6)	44 (86.3)
Length of stay, LOS (days)
<7	34 (19.4)	25 (22.5)	6 (11.8)
7–14	65 (37.1)	37 (33.3)	19 (37.3)
14–30	53 (30.3)	37 (33.3)	17 (33.3)
>30	23 (13.1)	12 (10.8)	9 (17.6)
Treatment
No treatment	11 (6.3)	8 (7.2)	1 (2.0)
First-line treatment	35 (20.0)	26 (23.4)	13 (25.5)
Rituximab	11 (6.3)	6 (5.4)	3 (5.9)
TPO receptor agonist	68 (38.9)	48 (43.2)	19 (37.3)
Other second-line treatment	50 (28.6)	23 (20.7)	15 (29.4)
Note: T0: at baseline, T1: at discharge, T2: at 3 months after discharge.

3.2 Fatigue during the follow-up period

The mean FACIT-F scores by patient characteristics across three data collection points are summarized in Table 2. At the time of enrollment in the present study, the mean (SD) score of FACIT-F was 37.2 (9.7). The score of FACIT-F had a rise at T1 (39.0 [8.8]) and tended to decrease to the level of baseline at T2 (34.7 [9.5]) (Fig. 1). In addition to the time factor, six factors were significantly associated with the FACIT-F score during follow-up (Table 4). Patients who were single, retired, had persistent ITP, splenomegaly had more severe fatigue, whereas those who had not received any prior treatment and had a bleeding score of 0 at admission had milder fatigue.

Table 2

The scores of FACIT-F in patients with ITP at all time-points
Characteristics	T0	T1	T2
Gender
Male	38.8 (8.5)	40.0 (7.8)	37.6 (8.4)
Female	36.4 (10.2)	38.6 (9.2)	33.1 (10.0)
P	0.244	0.662	0.148
Age (years)
18–29	39.1 (7.7)	42.3 (5.9)	37.1 (10.4)
30–39	36.8 (10.7)	37.6 (10.5)	37.3 (7.9)
40–49	35.5 (10.8)	37.7 (10.0)	36.4 (8.9)
50–59	37.5 (9.6)	38.7 (8.0)	27.8 (10.7)
≥ 60	37.5 (9.2)	39.4 (8.2)	36.0 (7.3)
P	0.822	0.512	0.136
Phase
Newly diagnosed	41.8 (6.7)	42.3 (7.0)	37.3 (8.1)
Persist	30.9 (9.6)	34.7 (8.0)	31.7 (9.3)
Chronic	37.9 (9.5)	40.1 (9.1)	35.6 (10.1)
P	<0.001	0.001	0.325
Previous treatment
No treatment	42.5 (7.0)	43.5 (5.0)	38.6 (5.6)
First-line	38.6 (7.4)	40.8 (8.2)	39.6 (9.5)
Second-line	35.7 (10.4)	37.5 (9.3)	33.5 (9.6)
P	0.171	0.102	0.102
Platelet level at admission(×10⁹/l)
<10	36.5 (10.2)	38.6 (9.2)	36.4 (9.4)
10–29	38.8 (8.8)	39.3 (7.9)	35.7 (8.2)
≥ 30	36.9 (10.5)	39.2 (10.0)	31.0 (11.1)
P	0.761	0.896	0.471
Bleeding scores at admission
0	39.5 (8.7)	41.2 (6.7)	35.7 (10.7)
1–2	37.4 (8.7)	39.7 (7.9)	37.1 (8.6)
>2	34.4 (11.3)	36.2 (10.8)	32.5 (8.9)
P	0.171	0.192	0.071
Number of other diseases
0	38.5 (9.1)	38.7 (9.2)	38.9 (7.3)
1–2	37.3 (9.8)	39.4 (8.4)	33.1 (9.4)
>2	34.8 (10.3)	38.3 (9.7)	36.0 (11.2)
P	0.245	0.916	0.396
Anemia
Yes	32.6 (12.9)	35.9 (11.2)	31.4 (8.5)
No	38.0 (8.9)	39.7 (8.2)	35.5 (9.6)
P	0.059	0.232	0.333
Splenomegaly
Yes	34.5 (8.7)	35.8 (10.5)	35.3 (12.6)
No	37.7 (9.8)	39.6 (8.4)	35.0 (9.1)
P	0.045	0.203	0.891
Length of stay, LOS (days)
<7	40.2 (7.8)	40.6 (7.8)	36.8 (4.4)
7–14	35.8 (10.1)	35.9 (11.2)	33.2 (9.4)
14–30	35.6 (10.2)	40.9 (6.4)	36.2 (11.8)
>30	40.0 (8.5)	39.6 (7.2)	35.7 (7.8)
P	0.054	0.313	0.612
Treatment
No treatment	43.9 (8.0)	42.1 (7.5)	45
First-line treatment	38.7 (8.7)	42.4 (7.8)	38.9 (5.3)
Rituximab	34.6 (11.7)	30.8 (13.9)	31.3 (17.0)
TPO receptor agonist	36.1 (9.0)	39.0 (7.9)	33.7 (10.9)
Other second-line treatment	36.6 (10.7)	36.3 (8.9)	33.5 (8.6)
P	0.078	0.019	0.353
Response during this treatment
No treatment	43.9 (8.0)	42.1 (7.5)	45
CR	37.5 (9.9)	41.2 (7.7)	36.7 (8.7)
PR	37.0 (9.6)	39.2 (8.6)	35.1 (9.4)
NR	35.2 (9.4)	33.6 (9.5)	31.2 (10.7)
P	0.032	0.005	0.246
Note: T0: at baseline, T1: at discharge, T2: at 3 months after discharge.

Table 3

The scores of ITP-PAQ in patients with ITP at all time-points
Characteristics	T0	T1	T2
Gender
Male	59.3 (19.7)	61.7 (19.5)	69.0 (16.6)
Female	56.9 (19.8)	59.7 (18.7)	59.8 (22.0)
P	0.244	0.662	0.148
Age (years)
18–29	59.0 (19.0)	59.7 (18.0)	70.1 (15.1)
30–39	58.4 (20.9)	58.9 (18.6)	60.7 (24.0)
40–49	55.3 (18.1)	58.5 (18.7)	66.5 (17.4)
50–59	57.0 (22.1)	57.8 (19.9)	49.5 (17.6)
≥ 60	59.6 (19.2)	65.7 (19.8)	80.0 (10.5)
P	0.822	0.512	0.136
Phase
Newly diagnosed	62.6 (17.5)	65.9 (16.8)	72.5 (16.1)
Persist	47.2 (18.1)	53.6 (15.7)	51.2 (18.9)
Chronic	60.1 (19.8)	61.8 (20.3)	65.5 (20.3)
P	<0.001	0.001	0.325
Previous treatment
No treatment	70.5 (17.6)	69.0 (15.3)	70.1 (22.1)
First-line	58.5 (19.3)	65.9 (15.9)	70.7 (14.9)
Second-line	55.0 (19.4)	56.7 (19.5)	61.2 (20.9)
P	0.171	0.102	0.102
Platelet level at admission(×10⁹/l)
<10	53.4 (20.1)	55.8 (19.9)	64.6 (18.9)
10–29	62.6 (18.9)	63.9 (17.5)	66.9 (19.4)
≥ 30	57.5 (18.9)	61.2 (18.7)	57.6 (24.5)
P	0.761	0.896	0.471
Bleeding scores at admission
0	60.8 (18.2)	62.6 (19.8)	61.7 (18.0)
1–2	59.1 (19.3)	62.8 (17.0)	70.1 (23.3)
>2	52.7 (21.1)	55.3 (19.6)	60.0 (18.9)
P	0.171	0.192	0.071
Number of other diseases
0	61.2 (17.7)	60.4 (16.5)	67.9 (17.1)
1–2	56.7 (20.4)	59.6 (19.6)	60.2 (22.5)
>2	54.6 (20.8)	61.9 (20.3)	69.1 (15.4)
P	0.245	0.916	0.396
Anemia
Yes	53.3 (19.2)	58.5 (19.6)	43.9 (18.7)
No	58.5 (19.8)	60.7 (18.8)	65.9 (19.3)
P	0.059	0.232	0.333
Splenomegaly
Yes	59.1 (19.4)	61.7 (17.4)	64.6 (17.4)
No	57.4 (19.8)	60.1 (19.2)	63.6 (20.8)
P	0.045	0.203	0.891
Length of stay, LOS (days)
<7	62.3 (19.0)	63.1 (17.9)	65.6 (16.0)
7–14	54.8 (18.6)	53.4 (17.3)	54.7 (20.8)
14–30	56.3 (21.7)	63.6 (20.2)	73.3 (20.2)
>30	62.3 (18.1)	65.6 (17.3)	63.7 (14.3)
P	0.185	0.045	0.041
Treatment
No treatment	73.5 (15.9)	73.6 (15.1)	81.3
First-line treatment	61.5 (18.9)	63.9 (18.7)	67.0 (20.6)
Rituximab	52.7 (19.9)	52.1 (18.2)	47.1 (34.1)
TPO receptor agonist	55.0 (19.5)	58.2 (19.0)	68.8 (17.0)
Other second-line treatment	56.3 (19.9)	58.2 (18.6)	56.7 (19.4)
P	0.041	0.123	0.338
Response during this treatment
No treatment	73.5 (15.9)	73.6 (15.1)	81.3
CR	59.3 (17.8)	62.4 (18.2)	67.7 (20.1)
PR	55.1 (23.1)	59.7 (20.7)	67.4 (17.5)
NR	54.1 (17.7)	52.5 (16.5)	50.1 (19.2)
P	0.026	0.024	0.082
Note: T0: at baseline, T1: at discharge, T2: at 3 months after discharge.

Table 4

Linear Mixed Models multivariate analysis of FACIT-F scores with demographic and clinical characteristics
Variable	Estimate	Standard error	P level	95% confidence interval, (lower, upper)
Intercept	37.47	3.52	<0.0001	(30.52, 44.43)
Timepoint (Reference: T0)
T1	2.48	0.69	<0.0001	(1.12, 3.85)
T2	-1.42	0.96	0.140	(-3.30, 0.47)
Gender (Reference: Female)
Male	0.29	1.34	0.830	(-2.36, 2.94)
Age, years (Reference: ≥60)
18–29	-0.36	2.70	0.894	(-5.70, 4.98)
30–39	-2.64	2.38	0.269	(-7.35, 2.06)
40–49	-4.18	2.25	0.065	(-8.63, 0.26)
50–59	-1.59	2.11	0.454	(-5.76, 2.59)
Marriage (Reference: Married)
Single	-3.77	1.86	0.044	(-7.45, -0.10)
Occupation (Reference: Unemployed)
Student	2.43	3.79	0.523	(-5.06, 9.92)
Employed	0.39	1.54	0.799	(-2.65, 3.44)
Retired	-4.95	2.45	0.045	(-9.79, -0.10)
Phase (Reference: Chronic)
Newly diagnosed	2.58	1.65	0.120	(-0.68, 5.84)
Persist	-5.20	1.54	0.001	(-8.24, -2.16)
Splenomegaly (Reference: No)
Yes	-4.12	1.70	0.017	(-7.49, -0.76)
Anemia (Reference: No)
Yes	-1.84	1.87	0.326	(-5.53, 1.85)
Number of other diseases (Reference: >2)
0	-1.41	1.94	0.468	(-5.24, 2.42)
1–2	0.42	1.68	0.802	(-2.90, 3.74)
Previous treatment (Reference: Second-line)
No treatment	5.72	1.91	0.003	(1.94, 9.49)
First-line	2.66	1.54	0.085	(-0.37, 5.70)
Bleeding scores at admission (Reference: >2)
0	4.52	1.62	0.006	(1.33, 7.71)
1–2	2.15	1.56	0.171	(-0.94, 5.23)
Platelet level at admission(×10⁹/l) (Reference: ≥30)
<10	1.94	1.78	0.277	(-1.57, 5.44)
10–29	0.61	1.80	0.735	(-2.95,4.17)
Length of stay, LOS (days) (Reference: >30)
<7	0.48	2.34	0.838	(-4.15, 5.11)
7–14	-2.28	1.97	0.248	(-6.17, 1.60)
14–30	-1.63	2.07	0.432	(-5.73, 2.46)
Treatment (Reference: Other second-line treatment)
No treatment	4.67	3.00	0.122	(-1.26, 10.59)
First-line treatment	1.63	1.90	0.394	(-2.13, 5.39)
Rituximab	-2.45	2.71	0.368	(-7.81, 2.91)
TPO receptor agonist	0.96	1.49	0.518	(-1.97, 3.90)
Note: T0: at baseline, T1: at discharge, T2: at 3 months after discharge.

3.3 HRQoL during the follow-up period

The mean ITP-PAQ scores by patient characteristics across three data collection points are summarized in Table 3. At the time of enrollment, the mean (SD) score of ITP-PAQ was 57.7 (19.7). The ITP-PAQ score gradually increased, achieving 60.3 (18.9) at T1 and 62.8 (20.0) at T2. (Fig. 1). Figure 2 summarizes trends in 10 subscales of ITP-PAQ at T0, T1, and T2. Notably, each subscale score of ITP-PAQ also tended to increase progressively, while significant differences only existed in the S, PH, and OQoL subscales. As shown in Table 5, patients with persistent ITP and those who have never received treatment for ITP have better HRQoL.

Table 5

Linear Mixed Models multivariate analysis of ITP-PAQ scores with demographic and clinical characteristics
Variable	Estimate	Standard error	P level	95% confidence interval, (lower, upper)
Intercept	62.97	8.34	<0.0001	(46.50, 79.45)
Timepoint (Reference: T0)
T1	2.48	1.13	0.029	(0.25, 4.71)
T2	7.32	1.57	<0.0001	(4.22, 10.42)
Gender (Reference: Female)
Male	1.77	3.18	0.579	(-4.51, 8.05)
Female	Ref
Age, years (Reference: ≥60)
18–29	-3.61	6.40	0.573	(-16.25, 9.03)
30–39	-6.57	5.65	0.247	(-17.73, 4.59)
40–49	-7.74	5.34	0.149	(-18.29, 2.80)
50–59	-7.08	4.99	0.158	(-16.94, 2.77)
Marriage (Reference: Married)
Single	-5.91	4.42	0.183	(-14.65, 2.82)
Occupation (Reference: Unemployed)
Student	0.71	9.14	0.939	(-17.38, 18.79)
Employed	0.99	3.67	0.787	(-6.26, 8.24)
Retired	-7.26	5.82	0.214	(-18.77, 4.25)
Phase (Reference: Chronic)
Newly diagnosed	1.76	3.90	0.652	(-5.95, 9.48)
Persist	-8.83	3.67	0.018	(-16.09, -1.57)
Splenomegaly (Reference: No)
Yes	3.28	4.04	0.418	(-4.70, 11.25)
Anemia (Reference: No)
Yes	0.46	4.45	0.917	(-8.33, 9.26)
Number of other diseases (Reference: >2)
0	0.34	4.60	0.942	(-8.76, 9.43)
1–2	-1.52	4.01	0.705	(-9.44, 6.40)
Previous treatment (Reference: Second-line)
No treatment	12.33	4.54	0.007	(3.35, 21.32)
First-line	4.17	3.66	0.256	(-3.06, 11.41)
Bleeding scores at admission (Reference: >2)
0	5.05	3.83	0.190	(-2.53, 12.62)
1–2	4.23	3.70	0.255	(-3.09, 11.55)
Platelet level at admission(×10⁹/l) (Reference: ≥30)
<10	-1.29	4.22	0.759	(-9.63, 7.04)
10–29	5.28	4.30	0.221	(-3.21, 13.78)
Length of stay, LOS (days) (Reference: >30)
<7	-5.43	5.57	0.331	(-16.43, 5.57)
7–14	-7.75	4.67	0.100	(-16.99, 1.49)
14–30	-5.92	4.93	0.232	(-15.67, 3.83)
Treatment (Reference: Other second-line treatment)
No treatment	13.82	7.11	0.054	(-0.24, 27.89)
First-line treatment	1.27	4.52	0.780	(-7.67, 10.20)
Rituximab	-4.61	6.42	0.474	(-17.29, 8.08)
TPO receptor agonist	0.25	3.52	0.944	(-6.71, 7.21)
Note: T0: at baseline, T1: at discharge, T2: at 3 months after discharge.

This longitudinal study assessed the changes in fatigue and HRQoL in ITP adults from admission to three months after discharge in China using FACIT-F and ITP-PAQ scales. This study provides the first evidence of longitudinal fatigue and HRQoL and influencing factors in adults with ITP in China. We found that hospitalized ITP adults’ fatigue improved at discharge but worsened at three months, while HRQoL gradually improved over time. The findings of this study can be used to help understand the fatigue and HRQoL over time in ITP patients, which helps clinical practitioners to precisely intervene to reduce patient fatigue and improve HRQoL.

The level of fatigue was moderate (mean FACIT-F score at baseline = 37.2) among the patients included in this study. This finding is similar to that of patients in a previous study in China (37.5) and a study in the United States (36.1), and slightly higher than that in a study conducted in Turkey and countries across the Asia Pacific and the Middle East (34.4) [18; 24]. The potential reason might be that the latter included participants of a clinical trial and had strict inclusion criteria rather than random selection [12; 18; 24]. In the present study, the mean fatigue score was highest at discharge and then decreased to a level that was similar to the baseline. This could be partly because the patient was temporarily away from work during hospitalization, so fatigue was relieved but resumed daily activities after discharge, which was aggravated compared with fatigue during hospitalization. A study in North America in 2020 showed that fatigue gradually improved by one month after treatments, and the improvement continued to be present at 12 months [25]. It is possible that the included patients were children, different from adults, and did not engage in daily physical and mental work, so their trend of fatigue was also different from that of adults. A 7-year follow-up in the United Kingdom showed that fatigue remained stable in ITP patients [26]. Differences between the duration of follow-up in our study and in that study might explain the divergent conclusion.

The HRQoL assessed by the ITP-PAQ was low among the patients in this study. Due to the lack of evidence on the total scores of ITP-PAQ, we only compared subscale scores with previous studies. Except for the activity (45.73 vs. 69.56), psychological (59.27 vs. 78.04), and overall quality of life (41.99 vs. 69.98), the scores of other subscales were comparable to a recent study in China [27]. Except for the lower scores of the subscales, such as bother (53.32 vs. 69.21), activity (45.73 vs. 64.11), fear (60.37 vs. 79.22), and overall quality of life (41.99 vs. 58.60) in our cohort, the scores of the other scales were comparable to a study in the US [20]. This reflects patients with ITP in our study had lower HRQoL levels than studies in China or abroad. Most studies included patients with varying severity of ITP, while the participants included in our study were mostly referred patients with difficult and severe ITP, so the HRQoL was lower. We also found persistent increases in HRQoL over time, which might be caused by adequate diagnosis and treatment at a professional medical facility, which can increase awareness and reduce anxiety.

Both FACIT-F and ITP-PAQ scores for persistent ITP in our study were lower than those in the newly diagnosed and chronic ITP groups, consistent with the results of previous studies [9; 12]. Patients with persistent ITP are in a transitional state between newly diagnosed ITP and chronic ITP. Due to a lack of understanding of the disease, they will be excessively worried about bleeding events in their daily life and limit daily activities, leading to impaired health. We assume that the newly diagnosed have not yet fully felt the impact of the disease on their lives, while the chronic has adapted to the disease state and has gained insight into disease knowledge after multiple visits. Previously untreated patients experienced less fatigue and better HRQoL than treated patients in our cohort. The drawbacks caused by treatment could not be ignored, such as the side effects of drugs, some intravenous invasive treatments, the need to maintain the stomach empty when oral eltrombopag was taken, missed work and school, and the limitation of social activities might cause fatigue and a decrease in the HRQoL.

This study also indicated that some demographic factors and bleeding scores were associated with fatigue. The single patients (including divorced patients) had higher fatigue compared with married patients because single patients received less social support than the married, and they could not get support from their partner for housework or work. This was consistent with the conclusion of the study of other diseases [28]. In addition, we found the retired had worse fatigue. Some patients in our study retired from the office because of ITP, and this population might have had a worse physical function, so the fatigue level was higher. We also found that the higher the bleeding score, that is, the more severe the bleeding symptoms, the more severe the fatigue. Bruising and bleeding could lead to anemia and iron deficiency, which were associated with fatigue, and bleeding limited daily activities and exercise, which might also cause fatigue [10]. Bruising and bleeding symptoms were also significantly associated with fatigue in univariate analysis of a postal survey [11].

No relationship was found between platelet count and fatigue or HRQoL in this study, which was consistent with previous studies that showed that platelet counts were not associated with fatigue in ITP patients [25; 26]. However, according to a previous study conducted in the US, 53% of patients are anxious about platelet counts, and clinicians must explain the risk of fatal bleeding caused by low platelets to patients in the clinic, which strengthens patients’ worries about low platelet levels [29]. More studies are needed to confirm the relationship between platelet level and fatigue or HRQoL.

Our study had some limitations. First, the number of patients was relatively limited in some subgroups, for example, only six patients were included in the “student” group. Second, patient attrition was an issue during the follow-up period. Dropouts in sample size during follow-up make it difficult to understand the role of various factors in HRQoL. A total of 57 questions might be too burdensome for repetitive measures over a short-time period. And the neglect of HRQoL among patients was also a reason for the loss of follow-up. At last, the follow-up time interval was relatively short, especially considering that ITP is a chronic disease, longer-term follow-up is needed to observe changes in patients’ HRQoL.

Adult patients with ITP in China have non-negligible impairment in fatigue and HRQoL, in addition to bleeding symptoms caused by thrombocytopenia. We found that patients’ fatigue improved at discharge but worsened at three months after discharge, while overall HRQoL and HRQoL in all subscales gradually improved over time. We also identified factors affecting fatigue and quality of life during follow-up, which help guide healthcare workers to administer appropriate interventions. For ITP patients, treatment outcomes such as bleeding manifestations and platelet count are essential, but HRQoL should also be emphasized. This would include a long follow-up of the patient to gain insight into the patient’s condition, not just around initial treatment, but how to manage the patient over the long term. Patient-reported outcomes are important measures to improve benefits from the intervention. Future studies should evaluate HRQoL as an important outcome measure to assess the benefits and risks of treatment.

Acknowledgment

The authors would like to thank all the participants for their time and effort. We also sincerely appreciate Yidu Cloud (Beijing) Technology Co., Ltd., China, for providing technical support in data extracting.

Ethnic approval

The ethnic approval was granted by the Ethics Committee at the Institute of Hematology and Blood Disease Hospital (IHBDH), Tianjin, China (Reference No. QTJC2022040-EC-1).

Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflict of interest

Renchi Yang has received speaker/consultancy fees from Bayer, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda. The remaining authors have no interests, which might be perceived as posing a conflict or bias. Yidu Cloud (Beijing) Technology Co., Ltd. had no impact on the study design and study results.

Funding

This project was supported in part by the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (No. 2019XK320075), and the CAMS Innovation Fund for Medical Sciences (CIFMS, No. 2021-I2M-1-003).

Authors’ contributions

Renchi Yang and Xiaofan Liu conceived and designed the research study. Wenhui Zhang wrote the first draft of the manuscript and analyzed/interpreted the data. Shitong Xie contributed to the manuscript preparation and data interpretation. Rongfeng Fu, Yunfei Chen, Wei Liu, Ting Sun, Mankai Ju, Huiyuan Li, Feng Xue, and Lei Zhang contributed to the acquisition and interpretation of data for the work. All authors critically reviewed and revised the manuscript. The final version of this manuscript was approved by all authors.

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No competing interests reported.

Longitudinal assessment of fatigue and health-related quality of life in adults with immune thrombocytopenia in China

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

1. Introduction

2. Methods