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Symptom Prevalence and Clustering of Symptoms in People Living with Chronic Hepatitis C Infection

  • Carolyn A. Lang
    Correspondence
    Address reprint requests to: Carolyn Lang, MPH, Center for Diabetes and Endocrine Research, The University of Queensland, c/o Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Ipswich Road, Brisbane, Australia 4102.
    Affiliations
    Center for Diabetes and Endocrine Research (C.A.L., G.A.M.) and School of Medicine (W.G.E.C.), The University of Queensland, Queensland; and School of Public Health (S.C., L.G., D.B., M.P.D.), Queensland University of Technology, Brisbane, Queensland, Australia
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  • Sue Conrad
    Affiliations
    Center for Diabetes and Endocrine Research (C.A.L., G.A.M.) and School of Medicine (W.G.E.C.), The University of Queensland, Queensland; and School of Public Health (S.C., L.G., D.B., M.P.D.), Queensland University of Technology, Brisbane, Queensland, Australia
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  • Lyndall Garrett
    Affiliations
    Center for Diabetes and Endocrine Research (C.A.L., G.A.M.) and School of Medicine (W.G.E.C.), The University of Queensland, Queensland; and School of Public Health (S.C., L.G., D.B., M.P.D.), Queensland University of Technology, Brisbane, Queensland, Australia
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  • Diana Battistutta
    Affiliations
    Center for Diabetes and Endocrine Research (C.A.L., G.A.M.) and School of Medicine (W.G.E.C.), The University of Queensland, Queensland; and School of Public Health (S.C., L.G., D.B., M.P.D.), Queensland University of Technology, Brisbane, Queensland, Australia
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  • W. Graham E. Cooksley
    Affiliations
    Center for Diabetes and Endocrine Research (C.A.L., G.A.M.) and School of Medicine (W.G.E.C.), The University of Queensland, Queensland; and School of Public Health (S.C., L.G., D.B., M.P.D.), Queensland University of Technology, Brisbane, Queensland, Australia
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  • Michael P. Dunne
    Affiliations
    Center for Diabetes and Endocrine Research (C.A.L., G.A.M.) and School of Medicine (W.G.E.C.), The University of Queensland, Queensland; and School of Public Health (S.C., L.G., D.B., M.P.D.), Queensland University of Technology, Brisbane, Queensland, Australia
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  • Graeme A. Macdonald
    Affiliations
    Center for Diabetes and Endocrine Research (C.A.L., G.A.M.) and School of Medicine (W.G.E.C.), The University of Queensland, Queensland; and School of Public Health (S.C., L.G., D.B., M.P.D.), Queensland University of Technology, Brisbane, Queensland, Australia
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      Abstract

      Quality of life has been shown to be poor among people living with chronic hepatitis C. However, it is not clear how this relates to the presence of symptoms and their severity. The aim of this study was to describe the typology of a broad array of symptoms that were attributed to hepatitis C virus (HCV) infection. Phase 1 used qualitative methods to identify symptoms. In Phase 2, 188 treatment-naïve people living with HCV participated in a quantitative survey. The most prevalent symptom was physical tiredness (86%) followed by irritability (75%), depression (70%), mental tiredness (70%), and abdominal pain (68%). Temporal clustering of symptoms was reported in 62% of participants. Principal components analysis identified four symptom clusters: neuropsychiatric (mental tiredness, poor concentration, forgetfulness, depression, irritability, physical tiredness, and sleep problems); gastrointestinal (day sweats, nausea, food intolerance, night sweats, abdominal pain, poor appetite, and diarrhea); algesic (joint pain, muscle pain, and general body pain); and dysesthetic (noise sensitivity, light sensitivity, skin problems, and headaches). These data demonstrate that symptoms are prevalent in treatment-naïve people with HCV and support the hypothesis that symptom clustering occurs.

      Key Words

      Introduction

      An estimated 170 million people, approximately 3% of the world's population, are infected with the hepatitis C virus (HCV).
      • World Health Organization
      Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium.
      HCV is one of the major causes of cirrhosis, liver cancer, and liver-related deaths. However, only a relatively small proportion of those infected with this virus will develop these life-threatening complications.
      • Kim W.R.
      • Brown Jr., R.S.
      • Terrault N.A.
      • et al.
      Burden of liver disease in the United States: summary of a workshop.
      The major impact of HCV for most people living with this virus is therefore likely to be on their quality of life (QOL).
      This issue has attracted considerable interest.
      • Davis G.
      • Balart L.A.
      • Schiff E.R.
      • et al.
      Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile.
      • Carithers Jr., R.L.
      • Sugano D.
      • Bayliss M.
      Health assessment for chronic HCV infection: results of quality of life.
      • Tong M.
      • el-Farra N.S.
      Clinical sequelae of hepatitis C acquired from injection drug use.
      • Lee D.
      • Jamal H.
      • Regenstein F.G.
      • et al.
      Morbidity of chronic hepatitis C as seen in a tertiary care medical center.
      • Foster G.R.
      • Goldin R.D.
      • Thomas H.C.
      Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis.
      • Bonkovsky H.L.
      • Woolley J.M.
      Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. The Consensus Interferon Study Group.
      • Neary M.
      • Cort S.
      • Bayliss M.S.
      • et al.
      Sustained virologic response is associated with improved health-related quality of life in relapsed chronic hepatitis C patients.
      • Rodger A.J.
      • Jolley D.
      • Thompson S.C.
      • et al.
      The impact of diagnosis of hepatitis C virus on quality of life.
      • Manns M.P.
      • McHutchinson J.G.
      • Gordon S.C.
      • et al.
      Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.
      • Younossi Z.M.
      Chronic liver disease and health-related quality of life.
      • Fontana R.J.
      • Hussain K.B.
      • Schwartz S.M.
      Emotional distress during interferon-alpha-2B and ribavirin treatment of chronic hepatitis C.
      • Bayliss M.S.
      • Gandek B.
      • Bungay K.M.
      • et al.
      A questionnaire to assess the generic and disease-specific health outcomes of patients with chronic hepatitis C.
      • Desmet V.J.
      • Gerber M.
      • Hoofnagle J.H.
      • et al.
      Classification of chronic hepatitis: diagnosis, grading and staging.
      • Hoofnagle J.H.
      Hepatitis C: the clinical spectrum of disease.
      • Gifford S.M.
      • O'Brien M.L.
      • Bammer G.
      • et al.
      Australian women's experiences of living with hepatitis C virus: Results from a cross-sectional survey.
      • Cotler S.J.
      • Wartelle C.F.
      • Larson A.M.
      • et al.
      Pretreatment symptoms and dosing regimen predict side-effects of interferon therapy for hepatitis C.
      These studies have demonstrated that health-related QOL (HRQOL) is relatively poor in people with HCV infection compared with controls, population normative data, or people with other liver diseases, and that HRQOL improves with eradication of the virus. These are important data, although many questions remain. It is not yet clear whether HCV infection has specific effects on health, or indeed whether there are typical symptoms. Further, if there are typical symptoms, we do not know if these are the primary reason for impaired QOL, or whether this is best explained by other factors in the lives of people living with HCV infection. Progress with these questions would be aided by a better understanding of the typology of symptoms.
      Only a small number of studies have addressed the issue of symptoms associated with HCV infection and this usually has not been the main focus of the research. Table 1 details the studies that have reported the prevalence of symptoms associated with HCV infection. Desmet et al.
      • Desmet V.J.
      • Gerber M.
      • Hoofnagle J.H.
      • et al.
      Classification of chronic hepatitis: diagnosis, grading and staging.
      in this early research, described the symptoms of chronic HCV as “typically mild, somewhat nonspecific and often overlooked” and reported fatigue as the most common symptom. Other studies have ascribed a variety of symptoms to hepatitis C including fatigue, malaise, myalgia, arthralgia, depression, fever, chills, nausea, vomiting and headache, abdominal pain, anorexia, vomiting, weight loss, rashes, and eye problems.
      • Tong M.
      • el-Farra N.S.
      Clinical sequelae of hepatitis C acquired from injection drug use.
      • Lee D.
      • Jamal H.
      • Regenstein F.G.
      • et al.
      Morbidity of chronic hepatitis C as seen in a tertiary care medical center.
      • Desmet V.J.
      • Gerber M.
      • Hoofnagle J.H.
      • et al.
      Classification of chronic hepatitis: diagnosis, grading and staging.
      • Hoofnagle J.H.
      Hepatitis C: the clinical spectrum of disease.
      • Gifford S.M.
      • O'Brien M.L.
      • Bammer G.
      • et al.
      Australian women's experiences of living with hepatitis C virus: Results from a cross-sectional survey.
      • Cotler S.J.
      • Wartelle C.F.
      • Larson A.M.
      • et al.
      Pretreatment symptoms and dosing regimen predict side-effects of interferon therapy for hepatitis C.
      • Barkhuizen A.
      • Rosen H.R.
      • Wolf S.
      • et al.
      Musculoskeletal pain and fatigue are associated with chronic hepatitis C: a report of 239 hepatology clinic patients.
      • Sladden T.
      • Hickey A.R.
      • Dunn T.M.
      • et al.
      Hepatitis C transmission on the north coast of NSW: explaining the unexplained.
      Table 1Summary of Published Studies of the Prevalence of Symptoms Attributed to HCV
      Fatigue/Physical TirednessArthralgiaMyalgiaNauseaAbdominal PainDepressionHeadache
      Desmet et al.,
      • Desmet V.J.
      • Gerber M.
      • Hoofnagle J.H.
      • et al.
      Classification of chronic hepatitis: diagnosis, grading and staging.
      Symptoms listed but no prevalence reported.
      Symptoms listed but no prevalence reported.
      Symptoms listed but no prevalence reported.
      Symptoms listed but no prevalence reported.
      Symptoms listed but no prevalence reported.
      Tong and el-Farra,
      • Tong M.
      • el-Farra N.S.
      Clinical sequelae of hepatitis C acquired from injection drug use.
      n=125
      >50%
      Hoofnagle,
      • Hoofnagle J.H.
      Hepatitis C: the clinical spectrum of disease.
      n=108
      62%19%31%
      Lee et al.,
      • Lee D.
      • Jamal H.
      • Regenstein F.G.
      • et al.
      Morbidity of chronic hepatitis C as seen in a tertiary care medical center.
      n=581
      45%17%
      Sladden et al.,
      • Sladden T.
      • Hickey A.R.
      • Dunn T.M.
      • et al.
      Hepatitis C transmission on the north coast of NSW: explaining the unexplained.
      n=219
      36%21%21%
      Barkhuizen et al.,
      • Barkhuizen A.
      • Rosen H.R.
      • Wolf S.
      • et al.
      Musculoskeletal pain and fatigue are associated with chronic hepatitis C: a report of 239 hepatology clinic patients.
      n=239
      56%42%38%
      Cotler et al.,
      • Cotler S.J.
      • Wartelle C.F.
      • Larson A.M.
      • et al.
      Pretreatment symptoms and dosing regimen predict side-effects of interferon therapy for hepatitis C.
      n=222
      25%6%5%3%2%12%
      Gifford et al.,
      • Gifford S.M.
      • O'Brien M.L.
      • Bammer G.
      • et al.
      Australian women's experiences of living with hepatitis C virus: Results from a cross-sectional survey.
      n=462
      44%13%
      Arthralgia and myalgia were combined.
      25%
      Nausea and abdominal pain were combined.
      a Symptoms listed but no prevalence reported.
      b Arthralgia and myalgia were combined.
      c Nausea and abdominal pain were combined.
      There are a number of limitations to these studies. Fatigue/physical tiredness was the only symptom mentioned in all studies. This was followed by arthralgia and myalgia, which were sometimes combined into one category, as were nausea and abdominal pain. In two of the studies,
      • Tong M.
      • el-Farra N.S.
      Clinical sequelae of hepatitis C acquired from injection drug use.
      • Lee D.
      • Jamal H.
      • Regenstein F.G.
      • et al.
      Morbidity of chronic hepatitis C as seen in a tertiary care medical center.
      symptomatology is not the main focus, and the data on symptoms are difficult to abstract. In general, it is not clear in these studies whether predefined lists of symptoms were used or if patients were asked to describe symptoms they attributed to HCV infection.
      • Tong M.
      • el-Farra N.S.
      Clinical sequelae of hepatitis C acquired from injection drug use.
      • Lee D.
      • Jamal H.
      • Regenstein F.G.
      • et al.
      Morbidity of chronic hepatitis C as seen in a tertiary care medical center.
      • Desmet V.J.
      • Gerber M.
      • Hoofnagle J.H.
      • et al.
      Classification of chronic hepatitis: diagnosis, grading and staging.
      • Hoofnagle J.H.
      Hepatitis C: the clinical spectrum of disease.
      • Gifford S.M.
      • O'Brien M.L.
      • Bammer G.
      • et al.
      Australian women's experiences of living with hepatitis C virus: Results from a cross-sectional survey.
      • Sladden T.
      • Hickey A.R.
      • Dunn T.M.
      • et al.
      Hepatitis C transmission on the north coast of NSW: explaining the unexplained.
      This distinction is important because the investigators may have compiled the symptom list and these therefore do not necessarily reflect the lived experience of HCV infection.
      The nature of clustering of symptoms is a new area of research. Exploratory factor analysis has been used to investigate symptoms clusters in cancer patients
      • Gift A.G.
      • Stommel M.
      • Jablonski A.
      • et al.
      A cluster of symptoms over time in patients with lung cancer.
      • Miaskowski C.
      • Dodd M.
      • Lee K.
      Symptom clusters: the new frontier in symptom management research.
      and patients with gastrointestinal symptoms,
      • Talley N.J.
      • Boyce P.
      • Jones M.
      Identification of distinct upper and lower gastrointestinal symptom groupings in an urban population.
      • Eslick G.D.
      • Howell S.C.
      • Hammer J.
      • et al.
      Empirically derived symptom sub-groups correspond poorly with diagnostic criteria for functional dyspepsia and irritable bowel syndrome. A factor and cluster analysis of a patient sample.
      while cluster analysis has been used to group patients according to symptoms.
      • Bartsch H.W.
      • Weis J.
      • Moser M.
      Cancer-related fatigue in patients attending oncological rehabilitation programs: prevalence, patterns and predictors.
      • Talley N.J.
      • Holtmann G.
      • Agreus L.
      • et al.
      Gastrointestinal symptoms and subjects cluster into distinct upper and lower groupings in the community: a four nations study.
      The identification and definition of symptom clusters in patients with cancer or chronic disease has the potential to impact on their treatment and pharmacotherapy.
      • Miaskowski C.
      • Dodd M.
      • Lee K.
      Symptom clusters: the new frontier in symptom management research.
      • Fleishman S.B.
      Treatment of symptom clusters: pain, depression, and fatigue.
      Anecdotally, from our clinical experience, patients with HCV appear to describe more severe symptoms than patients with other liver diseases; however, there is a paucity of data on this. Our aim was to describe the type, prevalence, and severity of symptoms in people living with HCV. In Phase 1 of this study, the aim was to determine the diversity of symptoms using a qualitative approach. The aim of Phase 2 was to examine symptom prevalence and severity in a broad-based sample of people living with hepatitis C and to delineate the types of symptom clusters that occur.

      Methods

      The Hepatitis C Quality of Life Project of the Queensland University of Technology and the University of Queensland was established to examine the impact of HCV infection on QOL. The study protocol conformed to the ethical guidelines of the 2000 Declaration of Helsinki and was approved by the following Human Research Ethics Committees: Queensland University of Technology; The Royal Brisbane and Women's Hospital; the Hospitals and Health Service Districts of Bundaberg, Cairns, Gold Coast, Gympie, Logan, Nambour, Redcliffe/Caboolture, Rockhampton, Toowoomba, Townsville; and the Prince Charles Hospital.

      Phase 1: Qualitative Assessment of QOL in HCV Infection

      The initial step in the research program was to form a Community Advisory Group (CAG) consisting of 14 stakeholders, including people with HCV infection, clinicians, nurses, and individuals from nongovernment and community-based organizations (see Acknowledgments). The CAG identified six broad QOL domains affected by HCV infection: physical, psychological, interpersonal/sexual, social, work/economic, and lifestyle issues. Based on these broad domains, 14 guiding questions were developed to elicit open-ended discussion in semistructured interviews (Appendix I).
      Participants were recruited who were identified as having HCV infection. They included people with medically acquired HCV, current and past injecting drug users, young people (<25 years old), people living in rural and urban Queensland, and male prisoners. This broad-based recruitment strategy was a deliberate attempt to examine the diversity of the lived experience of HCV infection.
      Focus groups and one-to-one interviews were recorded and transcribed verbatim. Transcripts were formatted for import into the qualitative analysis software, NUD∗IST V4 (Qualitative Solutions and Research, Melbourne, Victoria, Australia). NUD∗IST software supports data coding and organization in an index system and is an efficient data-handling tool for textual data such as interview transcripts.
      • Richards L.
      • Richards T.
      Computing in qualitative analysis: a healthy development?.
      In accordance with recognized techniques for the qualitative analysis of interviews, text was coded into categories relating to the six fields identified by the CAG.
      • Dey I.
      Qualitative data analysis: A user friendly guide for social sciences.
      In addition to coding predetermined categories, line-by-line coding was conducted so that all experiential concepts related to hepatitis C were coded, a process known as open coding.
      • Strauss A.
      • Corbin J.
      Basics of qualitative research: Techniques and procedures for developing grounded theory.
      The analysis resulted in a description of symptoms that formed the basis for the second phase of the project. The reliability of this approach was assessed by recontacting participants to confirm that the analysis had correctly identified relevant symptoms.

      Phase 2: Quantitative Assessment of Symptom Profile in HCV Infection

      Participants were recruited from a variety of agencies in urban and rural Queensland including hepatology outpatient clinics, blood coagulation disorder clinics, drug and alcohol services, and community support organizations (see Acknowledgments). Multiple methods were used to recruit participants, including approaches by clinic staff, community organization newsletters, recruitment flyers on notice boards, and by direct referral. All subjects had HCV antibodies confirmed by central review of pathology reports, although different commercial HCV antibody tests had been used in the various centers. Exclusion criteria included coinfection with hepatitis B or HIV/AIDS, or previous HCV treatment with interferon-based therapies, inability to provide informed consent, pregnancy, and age under 18 years. Finally, where HCV RNA was available, participants who were HCV RNA negative were excluded.
      Questionnaires were completed in one-to-one confidential interviews, with the questions asked in a standardized format by a single researcher (CL). Questions were included to assess the presence and severity of the 21 individual symptoms identified in Phase 1 (see Appendix II). Participants were shown a list of the symptoms and asked if they had experienced any of the symptoms in the previous 3 months. Participants were then shown a visual analogue scale (VAS) and asked to score the severity of each symptom at its worst in the last 3 months, with 0 being the symptom absent and 10 being the symptom experienced at its worst in the previous 3 months. To explore the phenomenon of “clustering of the symptoms” participants were asked if they had experienced episodes in the last 3 months where a group of these symptoms occurred together. In addition, there were questions relating to the mode and duration of HCV infection as well as basic demographic information.

      Statistical Analysis

      Data were analyzed with the Statistical Package for Social Sciences (SPSS) software package v11.0.0 using descriptive univariate analysis, Chi-squared (χ2) analysis, and Fisher's exact tests of measures of association where appropriate. The nonparametric Mann-Whitney U test was used to test for differences in the median symptom severity scores across gender, age group, and location (the transgender participant was excluded from all gender analyses). To examine whether any interrelationships existed between symptoms, a principal component analysis (PCA) with varimax rotation was performed on the VAS for the 21 individual symptoms. The assignment of individual symptoms to an independent factor was predicated by the highest factor loading score. Clinically meaningful labels were assigned by the authors to each of the factors. The internal consistency and reliability of the derived clusters from this analysis was assessed with Cronbach's α. Statistical significance was set at P<0.05 (two tailed).

      Results

      Phase 1

      The first phase of the study used qualitative methodologies to broadly determine the possible impact of HCV infection on QOL. Seventy-three people (25 females, 48 males; mean age=38 years, SD=9 years) with a diagnosis of hepatitis C infection were interviewed in one to one (n=20) and 12 group interviews (n=53). There was considerable diversity among participants in demographic and social background (Table 2).
      Table 2Characteristics of People Living with HCV Who Participated in Qualitative Phase 1 and Quantitative Phase 2 of the Study
      Phase 1, n=73Phase 2, n=188
      n (%)n (%)
      Gender
       Male48 (65.8)125 (66.5)
       Female25 (34.2)62 (33.0)
       Transgender0 (0)1 (0.5)
      Age39 (SD=9 years)42 (SD=10 years)
      Level of education
       University17 (23.3)29 (15.4)
       Trade/certificate16 (21.9)34 (18.1)
       Year 1215 (20.5)30 (16.0)
       <Year 1123 (31.5)95 (50.5)
      Income
       Wage/salary39 (53.4)67 (35.6)
       Partnership/business0 (0)17 (9.0)
       Pension/govt. benefit25 (34.2)99 (61.1)
       No income9 (12.3)5 (2.7)
      Location
       Metropolitan55 (75.3)115 (61.2)
       Non-Metropolitan14 (19.2)70 (37.2)
      Years since diagnosis
       <1 year4 (5.5)35 (18.6)
       1–540 (54.8)55 (29.3)
       6–1020 (27.4)44 (23.4)
       10+8 (11.0)41 (21.8)
      Analysis of the transcribed audiotaped interviews identified 21 symptoms that were mentioned by three or more participants (see left-hand column of Table 3). Symptoms ranged from those typically described in clinical literature (e.g., tiredness, nausea, food intolerance) to others that are rarely if ever mentioned, such as sleeping problems, night or day sweats, and hypersensitivity to light and noise. In addition, some participants volunteered that these symptoms tend to appear in distinct temporal clusters. One person described these as “hep C attacks.”
      Table 3Prevalence, Gender Differences, and Median Severity of Symptoms in People Living with Chronic Hepatitis C Infection
      Symptom Prevalence
      TotalMale, n=125Female, n=62Symptom Severity
      Symptom severity score: 1=“best you have felt” and 10=“the worst you have felt” in those who experienced the symptom.
      Symptomn (%)n (%)n (%)P Value
      Significance level 0.05 (two tailed).
      Median (min,max)
      Physical tiredness160 (85.6)101 (80.8)59 (95.2)0.0057 (2,10)
      Irritability139 (74.3)89 (71.2)50 (80.6)0.1116 (1,10)
      Depression130 (69.5)78 (62.4)52 (83.9)0.0026 (1,10)
      Mental tiredness130 (69.5)77 (61.6)53 (85.5)0.0017 (2,10)
      Abdominal pain128 (68.4)82 (65.6)46 (74.2)0.1536 (1,10)
      Forgetfulness122 (65.2)75 (60.0)47 (75.8)0.0235 (1,10)
      Sleep problems122 (65.4)79 (63.2)43 (69.4)0.2538 (2,10)
      Joint pain119 (63.6)83 (66.4)36 (58.1)0.1707 (1,10)
      Poor concentration115 (61.5)71 (56.8)44 (71.0)0.0426 (1,10)
      General body pain107 (57.2)70 (56.0)37 (59.7)0.3756 (1,10)
      Headaches104 (55.6)57 (45.6)47 (75.8)0.0004 (1,10)
      Muscle pain101 (54.0)67 (53.6)34 (54.8)0.4996 (2,10)
      Nausea99 (52.9)59 (47.2)40 (64.5)0.0185 (1,10)
      Poor appetite94 (50.3)59 (47.2)35 (56.5)0.1506 (1,10)
      Food intolerance90 (48.1)51 (40.8)39 (62.9)0.0035 (1,10)
      Diarrhea87 (46.5)56 (44.8)32 (50.0)0.3034 (1,10)
      Night sweats86 (46.0)55 (44.0)31 (50.0)0.2686 (1,10)
      Day sweats79 (42.2)46 (36.8)33 (53.2)0.0244 (1,10)
      Skin problems78 (41.7)47 (37.6)31 (50.0)0.0726 (1,10)
      Light sensitivity71 (38.0)36 (28.8)35 (56.5)0.0005 (1,10)
      Noise sensitivity69 (36.9)38 (30.4)31 (50.0)0.0076 (1,10)
      a Symptom severity score: 1=“best you have felt” and 10=“the worst you have felt” in those who experienced the symptom.
      b Significance level 0.05 (two tailed).

      Phase 2

      In the second phase, we sought to examine symptoms attributed to HCV in more depth, and participants were asked about the prevalence and severity of the 21 symptoms identified in Phase 1. One hundred and eighty-eight people living with chronic HCV infection participated (125 males, 62 females, and 1 transgender, mean age 42 years, SD=10 years; see Table 2).
      Table 3 shows the prevalence of the 21 symptoms and the median severity of those people who experienced the symptom. The 10 most prevalent symptoms in order were physical tiredness (86%), irritability (75%), depression (70%), mental tiredness (70%), abdominal pain (68%), forgetfulness (65%), sleep problems (65%), joint pain (64%), poor concentration (62%), and general body pain (57%). When present, the symptoms with the greater reported severity were sleep disturbance, physical tiredness, mental tiredness, and joint pain, while the median severity of all other symptoms was moderate (median severity 4 to 6).
      Four people (2.1%) experienced no symptoms within the 3 months prior to interview, 28 (15%) experienced between one and five symptoms, 80 (43%) experienced six to 14 symptoms, and 75 (40%) reported 15 or more symptoms. Thirty-three people (17%) experienced symptoms not listed in Table 3 including back pain; constipation; cramps; eye problems (spots, dry, or watery eyes); low libido; medication sensitivity; mood swings; night fevers; odor sensitivity; pruritus and other minor skin complaints; swelling, particularly of the lower limbs; throat problems; vertigo; and weight loss. Each of this latter group of symptoms was reported by fewer than three people and was not included in the subsequent analysis.
      Women were significantly (P<0.05) more likely than men to report physical tiredness (95% vs. 80%), depression (84% vs. 62%), mental tiredness (85% vs. 62%), headaches (76% vs. 46%), food intolerance (63% vs. 41%), sensitivity to light (57% vs. 29%) and noise (50% vs. 30%), as well as forgetfulness (76% vs. 60%), poor concentration (71% vs. 57%), nausea (65% vs. 47%), and day sweats (53% vs. 47%). One hundred sixteen participants (62%) reported that the symptoms tended to cluster together at various times (temporal clustering).

      Factor Analysis of Symptoms Attributable to HCV

      An exploratory PCA with varimax rotation was conducted (Table 4). The factor solution extracted four factors with Eigenvalues greater than 1. These factors accounted for 56.7% of the total variance.
      Table 4Factor Loadings from the PCA of Symptoms Attributed to Chronic HCV Infection
      SymptomNeuropsychiatricGastrointestinalAlgesicDysesthetic
      Mental tiredness0.7730.1430.1060.200
      Poor concentration0.7580.1990.1230.043
      Forgetfulness0.6930.0390.0740.223
      Depression0.6800.1910.0710.337
      Irritability0.6450.0970.1590.307
      Physical tiredness0.6000.2870.3400.093
      Sleep problems0.5820.2810.3140.024
      Day sweats0.2140.6650.176−0.151
      Nausea0.2670.6510.1190.289
      Food intolerance0.1100.6190.0870.250
      Night sweats0.3190.5870.266−0.112
      Abdominal pain0.1200.568−0.0040.444
      Poor appetite0.5040.5250.1090.194
      Diarrhea−0.1430.3950.2950.247
      Joint pain0.182−0.0000.8580.123
      Muscle pain0.2530.2770.7630.099
      General body pain0.2400.3140.6380.196
      Noise sensitivity0.2140.0120.1810.783
      Light sensitivity0.3150.0430.2800.656
      Skin problems0.2110.331−0.1680.494
      Headaches0.2250.2840.2160.472
      % of variance19.714.211.511.2
      Cronbach's α0.870.780.810.68
      Note: Entries in bold reveal the factor loadings for symptoms in each symptom cluster.
      Factor 1 represented a neurological/fatigue factor and accounted for 20% of the total variance. This factor contained the items mental tiredness, poor concentration, forgetfulness, depression, irritability, physical tiredness and sleep problems, and was labeled the neuropsychiatric cluster. Factor 2 consisted of a gastrointestinal group of symptoms and included nausea, food intolerance, abdominal pain, poor appetite, and diarrhea, as well as day and night sweats. This factor accounted for 14% of the total variance and was labelled the gastrointestinal cluster. Factor 3 consisted of a pain-related group of symptoms: joint pain, muscle pain, and general body pain. This factor, labelled the algesic cluster, explained 11% of the total variance. The last factor contained symptoms that conceptually appeared related to heightened sensitivity: noise sensitivity, light sensitivity, skin problems, and headaches. This group of symptoms (Factor 4) was labeled the dysesthetic cluster and accounted for 11% of the variance.
      The internal reliability of the four factors was assessed using Cronbach's α coefficient. Factors 1 and 3 demonstrated a high level of internal reliability (0.87 and 0.81, respectively). Factor 2 demonstrated good internal consistency (0.78) while Factor 4 was not quite as robust (0.68).

      Discussion

      The current study extends our clinical impression that individuals with HCV experience a variety of symptoms and that these symptoms are frequently perceived to have moderate to severe intensity. It highlights the high prevalence and severity of physical tiredness, irritability, depression, mental tiredness, and abdominal pain in people living with hepatitis C. In addition, the study identified several previously unreported symptoms including night sweats, day sweats, light sensitivity, and noise sensitivity. Identification of these latter symptoms was facilitated by the qualitative research approach used in Phase 1 of the project.
      Some of the symptoms we identified have been reported previously, particularly fatigue, nausea and abdominal pain,
      • Desmet V.J.
      • Gerber M.
      • Hoofnagle J.H.
      • et al.
      Classification of chronic hepatitis: diagnosis, grading and staging.
      • Hoofnagle J.H.
      Hepatitis C: the clinical spectrum of disease.
      • Gifford S.M.
      • O'Brien M.L.
      • Bammer G.
      • et al.
      Australian women's experiences of living with hepatitis C virus: Results from a cross-sectional survey.
      • Sladden T.
      • Hickey A.R.
      • Dunn T.M.
      • et al.
      Hepatitis C transmission on the north coast of NSW: explaining the unexplained.
      and myalgia and arthralgia.
      • Desmet V.J.
      • Gerber M.
      • Hoofnagle J.H.
      • et al.
      Classification of chronic hepatitis: diagnosis, grading and staging.
      • Cotler S.J.
      • Wartelle C.F.
      • Larson A.M.
      • et al.
      Pretreatment symptoms and dosing regimen predict side-effects of interferon therapy for hepatitis C.
      • Barkhuizen A.
      • Rosen H.R.
      • Wolf S.
      • et al.
      Musculoskeletal pain and fatigue are associated with chronic hepatitis C: a report of 239 hepatology clinic patients.
      The prevalence of symptoms in the current study is higher than in these earlier reports; this may reflect in part the strategy of asking about a specific list of symptoms. It is important to recognize that few participants (four) reported no symptoms. There are several potential explanations for this, other than the contribution from HCV infection. Many of these symptoms are experienced in everyday life, although there are no published data of the prevalence and severity in the general population.
      A number of host and viral factors could contribute to the presence of symptoms in people living with hepatitis C. Several studies have found evidence of direct effects of HCV on the central nervous system.
      • Forton D.M.
      • Thomas H.C.
      • Murphy C.A.
      • et al.
      Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease.
      • Kramer L.
      • Bauer E.
      • Funk G.
      • et al.
      Subclinical impairment of brain function in chronic hepatitis C infection.
      This could contribute to some of the symptoms, particularly those in the neuropsychiatric cluster. Similarly, several of the symptoms, fatigue in particular, could be a consequence of liver injury. Perceptions about hepatitis C could also contribute independently of virological and host factors: Rodger et al.
      • Rodger A.J.
      • Jolley D.
      • Thompson S.C.
      • et al.
      The impact of diagnosis of hepatitis C virus on quality of life.
      showed that several domains of QOL, as assessed by the Short Form-36, were impaired in people who were unaware that they had HCV infection; however, there was significantly more impairment among those who knew they were infected.
      There is a clear gender difference in the reporting of symptoms.
      • Waldron I.
      Sex differences in illness incidence, prognosis and mortality: issues and evidence.
      In the current study, women were more likely than men to report experiencing physical tiredness, mental tiredness, depression, forgetfulness, poor concentration, headaches, nausea, food intolerance day sweats, and sensitivity to light and noise. These differences in the pattern of symptom reporting are consistent with studies of other chronic diseases.
      • Gifford S.M.
      • O'Brien M.L.
      • Bammer G.
      • et al.
      Australian women's experiences of living with hepatitis C virus: Results from a cross-sectional survey.
      • Waldron I.
      Sex differences in illness incidence, prognosis and mortality: issues and evidence.
      • Robinson M.E.
      • Dannecker E.A.
      • George S.Z.
      • et al.
      Sex differences in the associations among psychological factors and pain report: a novel psychophysical study of patients with chronic low back pain.
      Symptom clusters have been identified in patients with cancer and other chronic diseases by using exploratory factor analytical techniques.
      • Miaskowski C.
      • Dodd M.
      • Lee K.
      Symptom clusters: the new frontier in symptom management research.
      • Eslick G.D.
      • Howell S.C.
      • Hammer J.
      • et al.
      Empirically derived symptom sub-groups correspond poorly with diagnostic criteria for functional dyspepsia and irritable bowel syndrome. A factor and cluster analysis of a patient sample.
      • Fleishman S.B.
      Treatment of symptom clusters: pain, depression, and fatigue.
      • Whitehead W.E.
      • Bassotti G.
      • Palsson O.
      • et al.
      Factor analysis of bowel symptoms in US and Italian populations.
      • Kwan A.C.-P.
      • Bao T.N.
      • Chakkaphak S.
      • et al.
      Validation of Rome II criteria for functional gastrointestinal disorders by factor analysis of symptoms in Asian patient sample.
      • Hammer J.
      • Howell S.
      • Bytzer P.
      • et al.
      Symptom clustering in subjects with and without diabetes mellitus: a population-based study of 15,000 Australian adults.
      • Gift A.G.
      • Jablonski A.
      • Stommel M.
      • et al.
      Symptom clusters in elderly patients with lung cancer.
      • Dodd M.J.
      • Miaskowski C.
      • Lee K.A.
      Occurrence of symptom clusters.
      PCA identified four related groups of symptoms in our sample. These symptom clusters were neuropsychiatric, gastrointestinal, algesic, and dysesthetic clusters. Each factor explained more than 10% of the variance and internal consistency, as measured with Cronbach's α for each of these four factors, was good. Additionally, the symptoms within clusters appear face valid as they are thematically related. This provides confidence that the symptom clusters are clinically meaningful and warrant further investigation. It should be emphasized that although the symptom clusters occur in the same individual, the symptoms in these clusters do not necessarily occur at the same time. The presence of symptoms occurring contemporaneously (i.e., clusters) was reported by 62% of our participants and warrants further investigation.
      Several limitations should be noted. First, although the aim of the qualitative phase was to encourage a broad discussion of the QOL of people with HCV infection, the questions we used to stimulate dialogue (see Appendix I) might have restricted the focus to specific types of problems. Second, we assessed symptom profiles in a broad-based sample of people with HCV, and for logistic reasons, HCV RNA studies were not performed. A proportion of the participants may have cleared the virus and therefore should no longer have viral impact on their QOL. Although we attempted to consecutively enrol all eligible subjects at the various centers, there was the potential for selection bias in recruitment, both by referring health care workers and the self-selection by participants who agreed to be interviewed.
      This study was not designed to determine whether symptoms and symptom clusters are specific to HCV. Studies to examine HCV RNA positive and negative patients, and the contributions of genotype, viral load, hepatic inflammation, and degree of fibrosis to symptom profile, may clarify this point. The main contributions of this paper are that we developed a list of symptoms attributed to HCV from qualitative interviews of people living with this virus, and using this list of symptoms identified four distinct clusters that statistically explain more than half the total variance in symptoms.
      In conclusion, people living with HCV experience a significant burden of symptoms in terms of both diversity and severity. The current study has identified four clusters of symptoms that occur in treatment-naïve patients. These data provide a basis for future studies to determine if these symptoms and clusters are more prevalent and severe in HCV than in other liver diseases or in healthy controls and to examine the host and virological factors that contribute to these symptoms.

      Acknowledgments

      The authors would like to acknowledge the following people: Ms. Rebecca Begbie, Ms. Kalie Bloxsom, Dr. Peter Boyd, Ms. Michelle Cook, Ms. Anna Cooney, Ms. Peta Deppeler, Ms. Mary Fenech, Ms. Anne Fisher, Mr. Patrick Gallagher, Ms. Lyn Gartlin, Ms. Prue Harding, Dr. John Hooper, Dr. Kate Hudson, Dr. Georgia Hume, Mr. Sean Keough, Ms. Mary Lafin, Ms. Sara Lane, Ms. Marlene Lear, Dr. Barbara Leggett, Mr. Patrick Martin, Dr. John Masson, Ms. Morag McColm, Ms. Karen McGill, Ms. Gillian McManus, Ms. Karen McWilliams, Dr. Case Nydham, Dr. George Ostapowicz, Dr. John Patton, Ms. Mary Potter, Dr. John Rowell, Prof. John Saunders, Ms. Ann Scott, Ms. Sue Sharman, Ms. Dottie St. Clair, Ms. Leanne Stone, Ms. Caroline Taylor, Mr. Jeff Ward, Dr. Nicola Weston, and Ms. Beryl Zeissink.
      The authors would also like to acknowledge the following organizations and affiliated Human Research Ethics Committees: Biala (Brisbane Community Health Center, The Prince Charles Hospital Health Service District); Brisbane Hemophilia Support Group; Brisbane Youth Services; Bundaberg Base Hospital; Cairns Base Hospital; Capricornia Youth Service; Gold Coast Hepatitis C Support Group; Gold Coast Hospital Health Service District; Gympie Hospital Health Service District; Hepatitis C Council of Queensland; Hervey Bay Women's Health Center; Kobi House (Toowoomba Hospital Health Services District); Logan Hospital; Mackay Base Hospital; Nambour Hospital; Princess Alexandra Hospital; Queensland Corrective Services; Queensland Intravenous AIDS Association; Redcliffe and Caboolture Health Service District; Royal Brisbane Hospital; The Center (Rockhampton); Sunshine Coast Injectors Voice and Action Group (SCIVAA); and Townsville Hospital Health Service District.

      Appendix I Guiding Questions for Phase 1 Interviews

      • 1.
        How do you personally define quality of life?
      • 2.
        What physical effects, if any, do you experience in relation to chronic hepatitis C infection?
      • 3.
        Are there problems with sleeping, like trouble getting to sleep, anxious waking, or waking up tired?
      • 4.
        If you experience fatigue, what kinds of things can you do to help you cope?
      • 5.
        Does hepatitis C affect your ability to concentrate or remember things?
      • 6.
        Have you noticed whether hepatitis C affects your moods?
      • 7.
        How does living with hepatitis C impact on your social life?
      • 8.
        What about work, or the ability to do things that you would normally do?
      • 9.
        What are the main economic costs of having this infection?
      • 10.
        How do you decide whom to tell about your hepatitis C?
      • 11.
        Does living with this virus affect intimate, personal relationships, including sex life?
      • 12.
        Do many people with hepatitis C suffer from discrimination?
      • 13.
        What do you think is behind the discrimination around hepatitis C?
      • 14.
        Are there any other ways that hepatitis C affects quality of life that we haven't discussed?

      Appendix II Symptom Checklist

      Looking now at the list of symptoms, which of these have you experienced in the last three months? On a scale of 0 to 10, with zero being the symptom absent, one being the best you have felt and 10 being the worst—How bad has your symptom been at its worst in the last three months—ON A SCALE OF 0 to 10.?
      Tabled 1
      Abdominal pain012345678910
      Day sweats012345678910
      Depression012345678910
      Diarrhea012345678910
      Food intolerance012345678910
      Forgetfulness012345678910
      General body pain012345678910
      Headaches012345678910
      Irritability012345678910
      Joint pain012345678910
      Light sensitivity012345678910
      Mental tiredness012345678910
      Muscle pain012345678910
      Nausea012345678910
      Night sweats012345678910
      Noise sensitivity012345678910
      Physical tiredness012345678910
      Poor appetite012345678910
      Poor concentration012345678910
      Skin problems012345678910
      Sleep problems012345678910
      Other symptoms012345678910
      [Please specify]

      References

        • World Health Organization
        Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium.
        J Viral Hepat. 1999; 6: 35-47
        • Kim W.R.
        • Brown Jr., R.S.
        • Terrault N.A.
        • et al.
        Burden of liver disease in the United States: summary of a workshop.
        Hepatology. 2002; 36: 227-242
        • Davis G.
        • Balart L.A.
        • Schiff E.R.
        • et al.
        Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile.
        Clin Ther. 1994; 16: 334-343
        • Carithers Jr., R.L.
        • Sugano D.
        • Bayliss M.
        Health assessment for chronic HCV infection: results of quality of life.
        Dig Dis Sci. 1996; 41: 75S-80S
        • Tong M.
        • el-Farra N.S.
        Clinical sequelae of hepatitis C acquired from injection drug use.
        West J Med. 1996; 164: 399-404
        • Lee D.
        • Jamal H.
        • Regenstein F.G.
        • et al.
        Morbidity of chronic hepatitis C as seen in a tertiary care medical center.
        Dig Dis Sci. 1997; 42: 186-191
        • Foster G.R.
        • Goldin R.D.
        • Thomas H.C.
        Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis.
        Hepatology. 1998; 27: 209-212
        • Bonkovsky H.L.
        • Woolley J.M.
        Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. The Consensus Interferon Study Group.
        Hepatology. 1999; 29: 264-270
        • Neary M.
        • Cort S.
        • Bayliss M.S.
        • et al.
        Sustained virologic response is associated with improved health-related quality of life in relapsed chronic hepatitis C patients.
        Semin Liver Dis. 1999; 19: 77-85
        • Rodger A.J.
        • Jolley D.
        • Thompson S.C.
        • et al.
        The impact of diagnosis of hepatitis C virus on quality of life.
        Hepatology. 1999; 30: 1299-1301
        • Manns M.P.
        • McHutchinson J.G.
        • Gordon S.C.
        • et al.
        Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.
        Lancet. 2001; 358: 958-965
        • Younossi Z.M.
        Chronic liver disease and health-related quality of life.
        Gastroenterology. 2001; 120: 305-307
        • Fontana R.J.
        • Hussain K.B.
        • Schwartz S.M.
        Emotional distress during interferon-alpha-2B and ribavirin treatment of chronic hepatitis C.
        Psychosomatics. 2002; 43: 378-385
        • Bayliss M.S.
        • Gandek B.
        • Bungay K.M.
        • et al.
        A questionnaire to assess the generic and disease-specific health outcomes of patients with chronic hepatitis C.
        Qual Life Res. 1998; 7: 39-55
        • Desmet V.J.
        • Gerber M.
        • Hoofnagle J.H.
        • et al.
        Classification of chronic hepatitis: diagnosis, grading and staging.
        Hepatology. 1994; 19: 1513-1520
        • Hoofnagle J.H.
        Hepatitis C: the clinical spectrum of disease.
        Hepatology. 1997; 26: 15S-20S
        • Gifford S.M.
        • O'Brien M.L.
        • Bammer G.
        • et al.
        Australian women's experiences of living with hepatitis C virus: Results from a cross-sectional survey.
        J Gastroenterol Hepatol. 2003; 18: 841-850
        • Cotler S.J.
        • Wartelle C.F.
        • Larson A.M.
        • et al.
        Pretreatment symptoms and dosing regimen predict side-effects of interferon therapy for hepatitis C.
        J Viral Hepat. 2000; 7: 211-217
        • Barkhuizen A.
        • Rosen H.R.
        • Wolf S.
        • et al.
        Musculoskeletal pain and fatigue are associated with chronic hepatitis C: a report of 239 hepatology clinic patients.
        Am J Gastroenterol. 1999; 94: 1355-1360
        • Sladden T.
        • Hickey A.R.
        • Dunn T.M.
        • et al.
        Hepatitis C transmission on the north coast of NSW: explaining the unexplained.
        Med J Aust. 1997; 166: 290-293
        • Gift A.G.
        • Stommel M.
        • Jablonski A.
        • et al.
        A cluster of symptoms over time in patients with lung cancer.
        Nurs Res. 2003; 52: 393-400
        • Miaskowski C.
        • Dodd M.
        • Lee K.
        Symptom clusters: the new frontier in symptom management research.
        J Natl Cancer Inst. 2004; 32: 17-21
        • Talley N.J.
        • Boyce P.
        • Jones M.
        Identification of distinct upper and lower gastrointestinal symptom groupings in an urban population.
        Gut. 1998; 42: 690
        • Eslick G.D.
        • Howell S.C.
        • Hammer J.
        • et al.
        Empirically derived symptom sub-groups correspond poorly with diagnostic criteria for functional dyspepsia and irritable bowel syndrome. A factor and cluster analysis of a patient sample.
        Aliment Pharmacol Ther. 2004; 19: 133-140
        • Bartsch H.W.
        • Weis J.
        • Moser M.
        Cancer-related fatigue in patients attending oncological rehabilitation programs: prevalence, patterns and predictors.
        Onkologie. 2003; 26: 51-57
        • Talley N.J.
        • Holtmann G.
        • Agreus L.
        • et al.
        Gastrointestinal symptoms and subjects cluster into distinct upper and lower groupings in the community: a four nations study.
        Am J Gastroenterol. 2000; 95: 1439-1447
        • Fleishman S.B.
        Treatment of symptom clusters: pain, depression, and fatigue.
        J Natl Cancer Inst. 2004; 2004: 119-123
        • Richards L.
        • Richards T.
        Computing in qualitative analysis: a healthy development?.
        Qual Health Res. 1991; 1: 234-262
        • Dey I.
        Qualitative data analysis: A user friendly guide for social sciences.
        Routledge, New York1993
        • Strauss A.
        • Corbin J.
        Basics of qualitative research: Techniques and procedures for developing grounded theory.
        2nd ed. Sage Publications, Thousand Oaks, CA1998
        • Forton D.M.
        • Thomas H.C.
        • Murphy C.A.
        • et al.
        Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease.
        Hepatology. 2002; 35: 433-439
        • Kramer L.
        • Bauer E.
        • Funk G.
        • et al.
        Subclinical impairment of brain function in chronic hepatitis C infection.
        J Hepatol. 2002; 37: 349-354
        • Waldron I.
        Sex differences in illness incidence, prognosis and mortality: issues and evidence.
        Soc Sci Med. 1983; 17: 1107-1123
        • Robinson M.E.
        • Dannecker E.A.
        • George S.Z.
        • et al.
        Sex differences in the associations among psychological factors and pain report: a novel psychophysical study of patients with chronic low back pain.
        J Pain. 2005; 6: 463-470
        • Whitehead W.E.
        • Bassotti G.
        • Palsson O.
        • et al.
        Factor analysis of bowel symptoms in US and Italian populations.
        Dig Liver Dis. 2003; 35: 774-783
        • Kwan A.C.-P.
        • Bao T.N.
        • Chakkaphak S.
        • et al.
        Validation of Rome II criteria for functional gastrointestinal disorders by factor analysis of symptoms in Asian patient sample.
        J Gastroenterol Hepatol. 2003; 18: 796-802
        • Hammer J.
        • Howell S.
        • Bytzer P.
        • et al.
        Symptom clustering in subjects with and without diabetes mellitus: a population-based study of 15,000 Australian adults.
        Am J Gastroenterol. 2003; 98: 391-398
        • Gift A.G.
        • Jablonski A.
        • Stommel M.
        • et al.
        Symptom clusters in elderly patients with lung cancer.
        Oncol Nurs Forum. 2004; 31: 202-212
        • Dodd M.J.
        • Miaskowski C.
        • Lee K.A.
        Occurrence of symptom clusters.
        J Natl Cancer Inst. 2004; : 76-78