Symptom assessment in hypereosinophilic syndrome: toward development of a patient-reported outcomes tool

Rare hypereosinophilic syndromes (HES) are a heterogeneous group of disorders characterized by peripheral and tissue eosinophilia resulting in a wide variety of clinical manifestations and distinct subtypes. Not only is HES heterogeneous from an etiologic perspective (i.e., comprised of myeloid, secondary and idiopathic disorders), but organ-system involvement is highly variable from patient to patient(1,2). Novel treatments including biologic therapies, may have differential effects on tissue depletion or eosinophil activation. Despite the recognition of HES and its pathologic presentations, few studies have assessed the patient experience or interviewed patients with the disease to date. A patient-reported outcomes (PRO) instrument measuring symptoms of HES would provide valuable information for use in clinical practice as well as inform endpoint selection and assessment of treatment effects in clinical trials (3,4). Although PRO’s have been developed in a wide variety of disorders, including both organ-restricted eosinophilic disorders (5) and disorders with heterogeneous, multisystem involvement, such as systemic lupus erythematosus (6), no PRO questionnaires developed specifically to measure the symptoms, disease impacts, or health-related quality-of-life (HRQoL) of patients with HES has been created due to the rarity of HES, the heterogeneity of clinical presentations, and confounding by the wide array of medications used to treat HES(1,2,7). Understanding the patient experience of disease is essential to support qualitative research and the development of PROs specific to HES. Accordingly, the main objective of the current study was to understand the HES patient’s symptoms, and disease experience for endpoint selection and PRO development for use in clinical care and clinical trials of novel therapies in accordance with the FDA PRO Guidance (3,4).

Literature review and concept elicitation interviews of 26 HES patients (Figure E4, Table E1–3) were used to understand important symptom concepts and impacts on HRQoL. A conceptual model with the goal of developing an HES-specific PRO instrument was constructed (Figure E3). Patients recruited from an IRB approved study for evaluation of patients with eosinophilic disease had standard assessments and were interviewed (see Online Repository for assessments, demographics and interview methods).

Patients reported a wide variety of symptoms (Figure 1), and impacts (Figure E2), and most patients experienced multiple HES symptoms over the course of their disease (median 12, SD 8.3). However, not all symptoms were present at the time of interview or were equally bothersome and physician assessed symptoms and patient reported symptoms differed (Figure E1). The most commonly reported symptom was fatigue (n=17, 65%), followed by itching (n=13, 50%). and shortness of breath (n=10, 38%) (Figure 1). Other common symptoms (present in >20% of patients) included abdominal pain, diarrhea, muscle pain, sinus congestion or rhinorrhea, chills or sweats, cough and wheezing. The most bothersome symptoms to patients varied considerably and depended on the organs affected; for example, most patients with dermatological involvement (n=17) reported itching as their most bothersome symptom, whereas those with GI involvement (n=12) more frequently reported abdominal pain. A variety of constitutional symptoms were reported including fatigue (n=17) which was described frequently as a “full body” sensation akin to “having the flu” or being “run over by a truck” accompanied by lack of desire to be active (n=6). Four patients described this as the most bothersome symptom of their HES. Physicians noted GI, cardiac, and sinus/nasal symptoms more than patients complained of symptoms referable to those organ systems. Conversely, patients often reported pulmonary, constitutional, musculoskeletal and neurologic/cognitive symptoms in the absence of documented objective evidence of eosinophilic organ involvement.

Figure 1.

Symptoms reported by HES patients

Nineteen patients (73%) reported that HES symptoms impacted their activities of daily living (ADLs), including their ability to get out of bed (n=6), perform chores (n=8), leave the house (n=7) or care for themselves (n=5) (Figure E2). Nine patients had to stop working temporarily or permanently due to their symptoms. HES affected all areas of patient functioning, with >80% of patients reporting an effect on their physical, emotional and social functioning (Figure 2). Some symptoms were associated with an emotional burden including “annoyance”, “frustration,” and associated feelings of depression and isolation. The most common functional impacts were on social activities (n=18, 69%), sleep (n=17, 65%) and walking (n=15, 58%). A majority of patients had been treated with glucocorticoids sometime during the course of their disease and most reported some side effects from their use.

Figure 2.

Patient-reported impact of HES on Social, Cognitive, Emotional and Physical functioning.

A draft conceptual model (Figure E3) depicts the impacts of the disease, the relationships among the impacts and compiles the effects of symptoms on patient functioning and well-being. The number of concepts and symptom domains identified precluded clustering of any one symptom or combination of symptoms for creation of a de-novo PRO with response options that reflect the totality of patient experience, whether between patients or for the same patient over time.

With the development of novel therapeutic agents that reduce or deplete blood eosinophils, it will be increasingly important to identify meaningful changes in disease activity and improvement in HES. The FDA PRO guidance issued in 2009(4) emphasizes use of metrics that would show improvement in how a patient “feels, functions, or survives.” Consistent with a prior multicenter study of 188 patients with HES (1), dermatologic, pulmonary and GI involvement were most common, although considerable inter-individual variability of reported symptoms, characterization of symptom experience, and recognition of the large burden of impact to ADLs and IADLs were identified supporting the need for additional efforts to develop safe and effective treatments for HES.

In summary, the present study highlights the difficulties in designing a measure sensitive enough to capture changes in PROs over time using a standard approach. Future efforts using other modalities, such as composite scoring systems utilizing validated instruments (e.g. PROMIS scales or HAQ subscales) or a most-bothersome symptom approach, that take into consideration the heterogeneity of HES and individual experiences of the disease are needed to advance efforts to create an HES-specific PRO.

Clinical Implications.

HES is a heterogenous disease with distinct subtypes, pathogenesis and myriad organ involvement and symptomatology making development of a patient reported outcome measure difficult. We describe the range of patient reported symptoms in a diverse group of HES patients.