Aritake S et al.：Prevalence of fatigue symptoms and correlations in the general adult population. Sleep and Biological Rhythms , 2015(13);146–154.
S M Lawrie, D N Manders, J R Geddes, A J Pelosi
A population-based incidence study of chronic fatigue.
Psychol Med. 1997 Mar;27(2):343-53.
Abstract/Text
BACKGROUND: Most research on syndromes of chronic fatigue has been conducted in clinical settings and is therefore subject to selection biases. We report a population-based incidence study of chronic fatigue (CF) and chronic fatigue syndrome (CFS).
METHODS: Questionnaires assessing fatigue and emotional morbidity were sent to 695 adult men and women who had replied to a postal questionnaire survey 1 year earlier. Possible CFS cases, subjects with probable psychiatric disorder and normal controls were interviewed.
RESULTS: Baseline fatigue score, the level of emotional morbidity and a physical attribution for fatigue were risk factors for developing CF. However, after adjusting for confounding, premorbid fatigue score was the only significant predictor. A minority of CF subjects, all female, had consulted their general practitioner; higher levels of both fatigue and emotional morbidity were associated with consultation. Possible CFS cases reported similar rates of current and past psychiatric disorder to psychiatric controls, but after controlling for fatigue or a diagnosis of neurasthenia the current rates were more similar to those of normal controls. Two new cases of CFS were confirmed.
CONCLUSIONS: Both fatigue and emotional morbidity are integral components of chronic fatigue syndromes. The demographic and psychiatric associations of CFS in clinical studies are at least partly determined by selection biases. Given that triggering and perpetuating factors may differ in CFS, studies that examine the similarities and differences between chronic fatigue syndromes and psychiatric disorder should consider both the stage of the illness and the research setting.
Judith A Ricci, Elsbeth Chee, Amy L Lorandeau, Jan Berger
Fatigue in the U.S. workforce: prevalence and implications for lost productive work time.
J Occup Environ Med. 2007 Jan;49(1):1-10. doi: 10.1097/01.jom.0000249782.60321.2a.
Abstract/Text
OBJECTIVE: The objective of this study was to estimate fatigue prevalence and associated health-related lost productive time (LPT) in U.S. workers.
METHODS: Fatigue prevalence, LPT due to fatigue, and LPT for any health-related reason (in hours and dollars) were measured in a national cross-sectional telephone survey of U.S. workers.
RESULTS: The 2-week period prevalence of fatigue was 37.9%. Of workers with fatigue, 65.7% reported health-related LPT compared with 26.4% of those without fatigue. Workers with fatigue cost employers 136.4 billion dollars annually in health-related LPT, an excess of 101.0 billion dollars compared with workers without fatigue. Fatigue frequently co-occurs with other conditions and, when present, is associated with a threefold increase, on average, in the proportion of workers with condition-specific LPT.
CONCLUSIONS: Fatigue is prevalent in the U.S. workforce. When occurring with other health conditions, it is associated with significantly more condition-specific LPT.
K Kroenke, D R Wood, A D Mangelsdorff, N J Meier, J B Powell
Chronic fatigue in primary care. Prevalence, patient characteristics, and outcome.
JAMA. 1988 Aug 19;260(7):929-34.
Abstract/Text
Although fatigue is one of the most common complaints in ambulatory care, research has been minimal. Of the 1159 consecutive patients surveyed in two adult primary-care clinics, 276 (24%) indicated that fatigue was a major problem. Fatigue was more prevalent in women than in men (28% vs 19%). Extensive clinical, laboratory, psychometric, and functional data were gathered for 102 fatigued patients and 26 controls. Laboratory testing was not useful in detecting unsuspected medical conditions or in determining the cause of fatigue. Depression or somatic anxiety or both were suggested by screening psychometric instruments in 82 fatigued patients (80%) compared with three controls (12%). Global dysfunction was marked, as reported by patients on the Sickness Impact Profile. The mean score on the Sickness Impact Profile of 11.3 for fatigued patients is similar to that reported for patients with major medical illnesses. After one year of follow-up, only 29 fatigued patients (28%) had improved. The high prevalence, persistence, and functional consequences of fatigue mandate a search for effective therapy.
P J Cathébras, J M Robbins, L J Kirmayer, B C Hayton
Fatigue in primary care: prevalence, psychiatric comorbidity, illness behavior, and outcome.
J Gen Intern Med. 1992 May-Jun;7(3):276-86.
Abstract/Text
OBJECTIVES: To identify the prevalence, psychiatric comorbidity, illness behavior, and outcome of patients with a presenting complaint of fatigue in a primary care setting.
METHODS: 686 patients attending two family medicine clinics on a self-initiated visit completed structured interviews for presenting complaints, self-report measures of symptoms and hypochondriasis, and the Diagnostic Interview Schedule (DIS). Fatigue was identified as a primary or secondary complaint from patient reports and questionnaires completed by physicians.
RESULTS: Of the 686 patients, 93 (13.6%) presented with a complaint of fatigue. Fatigue was the major reason for consultation of 46 patients (6.7%). Patients with fatigue were more likely to be working full or part time and to be French Canadian, but did not differ from the other clinic patients on any other sociodemographic characteristic or in health care utilization. Patients with fatigue received a lifetime diagnosis of depression or anxiety disorder more frequently than did other clinic patients (45.2% vs. 28.2%). Current psychiatric diagnoses, as indicted by the DIS, were limited to major depression, diagnosed for 16 (17.2%) fatigue patients. Patients with fatigue reported more medically unexplained physical symptoms, greater perceived stress, more pathologic symptom attributions, and greater worries about having emotional problems than did other patients. However, only those fatigue patients with coexisting depressive symptoms differed significantly from nonfatigue patients. Patients with fatigue lasting six months or longer compared with patients with more recent fatigue had lower family incomes and greater hypochondriacal worry. Duration of fatigue was not related to rate of current or lifetime psychiatric disorder. One half to two thirds of fatigue patients were still fatigued one year later.
CONCLUSIONS: In a primary care setting, only those fatigue patients who have coexisting psychological distress exhibit patterns of abnormal illness cognition and behavior. Regardless of the physical illnesses associated with fatigue, psychiatric disorders and somatic amplification may contribute to complaints of fatigue in less than 50% of cases presented to primary care.
D Buchwald, P Umali, J Umali, P Kith, T Pearlman, A L Komaroff
Chronic fatigue and the chronic fatigue syndrome: prevalence in a Pacific Northwest health care system.
Ann Intern Med. 1995 Jul 15;123(2):81-8.
Abstract/Text
OBJECTIVES: To investigate the point prevalence of the chronic fatigue syndrome and unexplained debilitating chronic fatigue in a community-based sample of persons and to describe demographic, clinical, and psychosocial differences among those with the chronic fatigue syndrome, those with chronic fatigue, and healthy controls.
DESIGN: Prospective cohort study.
SETTING: A health maintenance organization in Seattle, Washington.
PARTICIPANTS: A random sample of 4000 members of the health maintenance organization was surveyed by mail for the presence of chronic fatigue.
MEASUREMENTS: Persons with chronic fatigue were evaluated using a questionnaire that requested information about medical history and fatigue and related symptoms; validated measures of functional status and psychological distress; a physical examination; and standardized blood tests. A structured psychiatric interview was done in persons who appeared to meet the original Centers for Disease Control and Prevention (CDC) criteria for the chronic fatigue syndrome. Participants completed self-report measures at 12 and 24 months. Those with chronic fatigue were reevaluated in person 1 year after study enrollment.
RESULTS: 3066 (77%) of the 4000 members surveyed responded. Chronic fatigue was reported by 590 persons (19%). Of these, 388 (66%) had a medical or psychiatric condition that could account for the fatigue. Of the 74 persons (37%) with chronic fatigue who were enrolled in the study, only 3 met the CDC criteria for the chronic fatigue syndrome. The remaining 71 persons were designated as having chronic fatigue alone. Seventy-four healthy, age- and sex-matched controls who were drawn from the same sample but who denied having chronic fatigue were also studied. Demographic characteristics were similar in persons with the chronic fatigue syndrome, persons with chronic fatigue alone, and controls. Those with the chronic fatigue syndrome or chronic fatigue alone had more frequent cervical and axillary adenopathy, poorer functional status, and greater psychological distress than controls. Women and minorities were not overrepresented among cases with chronic fatigue.
CONCLUSIONS: Using different assumptions about the likelihood that persons who did not participate in the study had the chronic fatigue syndrome, the estimated crude point prevalence of the syndrome in this community ranged from 75 to 267 cases per 100,000 persons. The point prevalence of chronic fatigue alone was strikingly higher; it ranged from 1775 to 6321 cases per 100,000 persons.
C H Bombardier, D Buchwald
Outcome and prognosis of patients with chronic fatigue vs chronic fatigue syndrome.
Arch Intern Med. 1995 Oct 23;155(19):2105-10.
Abstract/Text
BACKGROUND: There are few data on the natural history and prognosis of persons with chronic fatigue (CF) or CF syndrome (CFS). Therefore, we compared functional outcomes in patients with each condition and tested the validity of various prognostic indicators.
METHODS: Four hundred forty-five (89%) of 498 consecutive referral patients were surveyed an average of 1.5 years after an initial evaluation. Data from the initial evaluation were used to predict outcomes.
RESULTS: Sixty-four percent of all patients reported improvement, but only 2% reported complete resolution of symptoms. Patients initially diagnosed as having CFS reported greater symptom severity and lower level of functioning at follow-up than did patients with CF. Major depression predicted unemployment in the CF group. Older age, longer duration of illness, and a lifetime history of dysthymia predicted less improvement in the CF group. Current dysthymia predicted less improvement for the CFS group.
CONCLUSIONS: The case definition of CFS according to the Centers for Disease Control and Prevention identifies chronically fatigued patients with poorer prognosis. In a tertiary care setting, recovery from CF or CFS is rare, but improvement is common. Prognostic indicators vary for the two groups, but the coexistence of dysthymia suggests poorer outcomes generally.
P Manu, T J Lane, D A Matthews
The frequency of the chronic fatigue syndrome in patients with symptoms of persistent fatigue.
Ann Intern Med. 1988 Oct 1;109(7):554-6.
Abstract/Text
STUDY OBJECTIVE: To determine the frequency of the chronic fatigue syndrome among patients with symptoms of fatigue.
DESIGN: Prospective, cohort study.
SETTING: Referral clinic, based in a primary care general internal medicine faculty practice of a university medical center.
PATIENTS: Consecutive sample of 135 patients (53 men, 82 women) with 6 months or more of debilitating fatigue.
INTERVENTIONS: All patients had a complete history taken, had a physical examination and a comprehensive battery of blood tests, and were given the Diagnostic Interview Schedule of the National Institute of Mental Health, a highly-structured 260-item instrument designed to enable accurate psychiatric diagnoses. Other diagnostic studies (for example, sleep studies and electroencephalography) were ordered if necessary for individual patients.
MEASUREMENTS AND MAIN RESULTS: Six of the one hundred thirty-five patients met criteria for chronic fatigue syndrome (95% CI, 0 to 10). Ninety-one (67%) patients (CI, 56 to 78) had clinically active psychiatric disorders and 4 (3%) patients (CI, 0 to 8) had medical disorders that were considered a major cause of their fatigue. Thirty-four (25%) patients (CI, 14 to 36) had insufficient symptoms or objective findings of the chronic fatigue syndrome.
CONCLUSION: The chronic fatigue syndrome is rare among patients with symptoms of persistent fatigue. Most of these patients have psychiatric disorders.
Kelvin K F Tsoi, Joyce Y C Chan, Hoyee W Hirai, Samuel Y S Wong
Comparison of diagnostic performance of Two-Question Screen and 15 depression screening instruments for older adults: systematic review and meta-analysis.
Br J Psychiatry. 2017 Apr;210(4):255-260. doi: 10.1192/bjp.bp.116.186932. Epub 2017 Feb 16.
Abstract/Text
BackgroundScreening for depression in older adults is recommended.AimsTo evaluate the diagnostic accuracy of the Two-Question Screen for older adults and compare it with other screening instruments for depression.MethodWe undertook a literature search for studies assessing the diagnostic performance of depression screening instruments in older adults. Combined diagnostic accuracy including sensitivity and specificity were the primary outcomes. Potential risks of bias and the quality of studies were also assessed.ResultsA total of 46 651 participants from 133 studies were identified evaluating 16 screening instruments. The majority of studies (64/133) used various versions of the Geriatric Depression Scale (GDS) and 6 used the Two-Question Screen. The combined sensitivity and specificity for the Two-Question Screen were 91.8% (95% CI 85.2-95.6) and 67.7% (95% CI 58.1-76.0), respectively; the diagnostic performance area under the curve (AUC) was 90%. The Two-Question Screen showed comparable performance with other instruments, including clinician-rated scales. The One-Question Screen showed the lowest diagnostic performance with an AUC of 78%. In subgroup analysis, the Two-Question Screen also had good diagnostic performance in screening for major depressive disorder.ConclusionsThe Two-Question Screen is a simple and short instrument for depression screening. Its diagnostic performance is comparable with other instruments and, therefore, it would be favourable to use it for older adult screening programmes.
© The Royal College of Psychiatrists 2017.
Bruce Arroll, Natalie Khin, Ngaire Kerse
Screening for depression in primary care with two verbally asked questions: cross sectional study.
BMJ. 2003 Nov 15;327(7424):1144-6. doi: 10.1136/bmj.327.7424.1144.
Abstract/Text
OBJECTIVE: To determine the diagnostic accuracy of two verbally asked questions for screening for depression.
DESIGN: Cross sectional criterion standard validation study.
SETTING: 15 general practices in New Zealand.
PARTICIPANTS: 421 consecutive patients not taking psychotropic drugs.
MAIN OUTCOME MEASURES: Sensitivity, specificity, and likelihood ratios of the two questions compared with the computerised composite international diagnostic interview.
RESULTS: The two screening questions showed a sensitivity and specificity of 97% (95% confidence interval, 83% to 99%) and 67% (62% to 72%), respectively. The likelihood ratio for a positive test was 2.9 (2.5 to 3.4) and the likelihood ratio for a negative test was 0.05 (0.01 to 0.35). Overall, 37% (157/421) of the patients screened positive for depression.
CONCLUSION: Two verbally asked questions for screening for depression would detect most cases of depression in general practice. The questions have the advantage of brevity. As treatment is more likely when doctors make the diagnosis, these questions may have even greater utility.
T J Lane, D A Matthews, P Manu
The low yield of physical examinations and laboratory investigations of patients with chronic fatigue.
Am J Med Sci. 1990 May;299(5):313-8.
Abstract/Text
Fatigue is a common symptom but guidelines for its appropriate evaluation are lacking. The authors prospectively studied 100 adults with a chief complaint of fatigue lasting at least 1 month in order to determine the diagnostic contribution of physical examinations and laboratory investigations. The evaluations were performed in the specialized clinic of a faculty practice. Physical examinations produced diagnostic information in 2% of patients, and laboratory investigations elucidated the cause of fatigue in 5% of patients. Structured follow-up evaluations after an average interval of 10 months failed to reveal any new organic causes for the fatigue symptom. Minor laboratory abnormalities were relatively common but did not contribute to the diagnostic process and did not seem to influence the clinical outcome. The authors conclude that the traditional medical evaluation of patients complaining of chronic fatigue has a low yield in discovering treatable physical disorders.
S Wessely, T Chalder, S Hirsch, P Wallace, D Wright
Psychological symptoms, somatic symptoms, and psychiatric disorder in chronic fatigue and chronic fatigue syndrome: a prospective study in the primary care setting.
Am J Psychiatry. 1996 Aug;153(8):1050-9.
Abstract/Text
OBJECTIVE: This study assessed relationships among psychological symptoms, past and current psychiatric disorder, functional impairment, somatic symptoms, chronic fatigue, and chronic fatigue syndrome.
METHOD: A prospective cohort study was followed by a nested case-control study. The subjects, aged 18-45 years, had been in primary care for either clinical viral infections or a range of other problems. Questionnaire measures of fatigue and psychological symptoms were completed by 1,985 subjects 6 months later; 214 subjects with chronic fatigue were then compared with 214 matched subjects without fatigue. Assessments were made with questionnaires, interviews, and medical records of fatigue, somatic symptoms, psychiatric disorder, and functional impairment.
RESULTS: Subjects with chronic fatigue were at greater risk than those without chronic fatigue for current psychiatric disorder assessed by standardized interview (60% versus 19%) or by questionnaire (71% versus 31%). Chronic fatigue subjects were more likely to have received psychotropic medication or experienced psychiatric disorder in the past. There was a trend for previous psychiatric disorder to be associated with comorbid rather than noncomorbid chronic fatigue. Most subjects with chronic fatigue syndrome also had current psychiatric disorder when assessed by interview (75%) or questionnaire (78%). Both the prevalence and incidence of chronic fatigue syndrome were associated with measures of previous psychiatric disorder. The number of symptoms suggested as characteristics of chronic fatigue syndrome was closely related to the total number of somatic symptoms and to measures of psychiatric disorder. Only postexertion malaise, muscle weakness, and myalgia were significantly more likely to be observed in chronic fatigue syndrome than in chronic fatigue.
CONCLUSIONS: Most subjects with chronic fatigue or chronic fatigue syndrome in primary care also meet criteria for a current psychiatric disorder. Both chronic fatigue and chronic fatigue syndrome are associated with previous psychiatric disorder, partly explained by high rates of current psychiatric disorder. The symptoms thought to represent a specific process in chronic fatigue syndrome may be related to the joint experience of somatic and psychological distress.
P Manu, T J Lane, D A Matthews
Chronic fatigue and chronic fatigue syndrome: clinical epidemiology and aetiological classification.
Ciba Found Symp. 1993;173:23-31; discussion 31-42.
Abstract/Text
To determine the medical and psychiatric diagnoses that have an aetiological role in chronic fatigue we conducted a prospective study of 405 (65% women) patients who presented for evaluation with this chief complaint to an academic medical centre. The average age was 38.1 years and the average duration of fatigue at entry in the study was 6.9 years. All patients were given comprehensive physical and laboratory evaluations and were administered a highly structured psychiatric interview. Psychiatric diagnoses explaining the chronic fatigue were identified in 74% of patients and physical disorders were diagnosed in 7% of patients. The most common psychiatric conditions in this series were major depression, diagnosed in 58% of patients, panic disorder, diagnosed in 14% of patients, and somatization disorder, diagnosed in 10% of patients. Primary sleep disorders, diagnosed in 2% patients, and chronic infections, confirmed in 1.6% patients, explained the majority of cases whose chronic fatigue was attributed to a physical disorder. Thirty per cent of patients met the criteria used to define the chronic fatigue syndrome (CFS). Compared with age- and gender-matched control subjects with chronic fatigue, CFS patients had a similarly high prevalence of current psychiatric disorders (78% versus 82%), but were significantly more likely to have somatization disorder (28% versus 5%) and to attribute their illness to a viral infection (70% versus 33%). We conclude that most patients with a chief complaint of chronic fatigue, including those exhibiting the features of CFS, suffer from standard mood, anxiety and/or somatoform disorders. Careful research is still needed to determine whether CFS is a distinct entity or a variant of these psychiatric illness.
Jack D Edinger, William S Sampson
A primary care "friendly" cognitive behavioral insomnia therapy.
Sleep. 2003 Mar 15;26(2):177-82.
Abstract/Text
OBJECTIVES: This study was conducted to test the effectiveness of an abbreviated cognitive-behavioral insomnia therapy (ACBT) with primary
DESIGN: A single-blind, randomized group design was used in which study patients were randomized to either a brief, 2-session ACBT or a similarly brief intervention (SHC) that included only generic sleep hygiene recommendations.
SETTING: A university-affiliated Department of Veterans Affairs medical center.
PARTICIPANTS: Twenty (2 women) veteran patients (M(age) = 51.0 yrs., SD = 13.7 years) who met criteria for chronic primary insomnia.
MEASUREMENTS AND RESULTS: Participants completed sleep logs for 2 weeks and questionnaires to measures insomnia symptoms, sleep-related self-efficacy, and dysfunctional beliefs about sleep before treatment, during a 2-week posttreatment assessment, and again at a 3-month posttreatment follow-up. Statistical analyses showed that ACBT produced significantly larger improvements across a majority of outcome measures than did SHC. Case-by-case analyses showed that only the ACBT produced consistent positive effects across study patients, and a sizeable proportion of these patients receiving this treatment achieved clinically significant improvements by their study endpoints. Approximately 52% of those receiving the ACBT reported at least a 50% reduction in their wake time after sleep onset, and 55.6% of ACBT-treated patients who entered the study with pathologic scores on an Insomnia Symptom Questionnaire (ISQ), achieved normal ISQ scores by their final outcome assessment.
CONCLUSIONS: ACBT is effective for reducing subjective sleep disturbance and insomnia symptoms in primary care patients.
Hung-Yuan Chen, Chih-Kang Chiang, Hsi-Hao Wang, Kuan-Yu Hung, Yue-Joe Lee, Yu-Sen Peng, Kwan-Dun Wu, Tun-Jun Tsai
Cognitive-behavioral therapy for sleep disturbance in patients undergoing peritoneal dialysis: a pilot randomized controlled trial.
Am J Kidney Dis. 2008 Aug;52(2):314-23. doi: 10.1053/j.ajkd.2008.03.012. Epub 2008 May 29.
Abstract/Text
BACKGROUND: Greater than 50% of dialysis patients experience sleep disturbances. Cognitive-behavioral therapy (CBT) is effective for treating chronic insomnia, but its effectiveness has never been reported in peritoneal dialysis (PD) patients and its association with cytokines is unknown. We investigated the effectiveness of CBT in PD patients by assessing changes in sleep quality and inflammatory cytokines.
STUDY DESIGN: Randomized control study with parallel-group design.
SETTING & PARTICIPANTS: 24 PD patients with insomnia in a tertiary medical center without active medical and psychiatric illness were enrolled.
INTERVENTION: The intervention group (N = 13) received CBT from a psychiatrist for 4 weeks and sleep hygiene education, whereas the control group (N = 11) received only sleep hygiene education.
OUTCOMES & MEASUREMENTS: Primary outcomes were changes in the Pittsburgh Sleep Quality Index and Fatigue Severity Scale scores, and secondary outcomes were changes in serum interleukin 6 (IL-6), IL-1beta, IL-18, and tumor necrosis factor alpha levels during the 4-week trial.
RESULTS: Median percentages of change in global Pittsburgh Sleep Quality Index scores were -14.3 (interquartile range, -35.7 to - 6.3) and -1.7 (interquartile range, -7.6 to 7.8) in the intervention and control groups, respectively (P = 0.3). Median percentages of change in global Fatigue Severity Scale scores were -12.1 (interquartile range, -59.8 to -1.5) and -10.5 (interquartile range, -14.3 to 30.4) in the intervention and control groups, respectively (P = 0.04). Serum IL-1beta level decreased in the intervention group, but increased in the control group (P = 0.04). There were no significant differences in changes in other cytokines.
LIMITATIONS: This study had a small number of participants and short observation period, and some participants concurrently used hypnotics.
CONCLUSIONS: CBT may be effective for improving the quality of sleep and decreasing fatigue and inflammatory cytokine levels. CBT can be an effective nonpharmacological therapy for PD patients with sleep disturbances.
Michael T Smith, David N Neubauer
Cognitive behavior therapy for chronic insomnia.
Clin Cornerstone. 2003;5(3):28-40.
Abstract/Text
Approximately 20% of patients presenting in general medical settings have severe and persistent insomnia. Studies consistently find that trouble initiating and maintaining sleep are independent risk factors for medical and psychiatric morbidity, but insomnia is often underdetected and undertreated in primary care settings. Cognitive-behavioral treatment approaches for chronic insomnia and related sleep disorders have been shown to be effective in various patient populations. This article reviews the most common cognitive-behavioral interventions for insomnia, and discusses their efficacy and durability. Possible adaptations for the integration of these approaches into primary care settings and a description of the emerging field of behavioral sleep medicine as a resource for health care providers treating patients with chronic insomnia are also presented.
C Guilleminault, A Clerk, J Black, M Labanowski, R Pelayo, D Claman
Nondrug treatment trials in psychophysiologic insomnia.
Arch Intern Med. 1995 Apr 24;155(8):838-44.
Abstract/Text
BACKGROUND: Due to a variety of potential problems with long-term hypnotic use, patients and treating physicians often try to avoid drugs in the treatment of psychophysiologic insomnia and to use nondrug treatment strategies, but these treatments must bring relief within a limited amount of time to be acceptable to patients.
METHOD: Thirty patients participated in the study. All had, for a minimum of 6 months, the complaint of less than 6 hours total sleep time per night in conjunction with either: (1) spending more than 30 minutes in bed before falling asleep, or (2) awakening during the night within 2 hours of sleep onset with difficulty returning to sleep. All subjects had the associated complaint of daytime impairment and none had used hypnotics for at least 3 months. Patients were randomly assigned to three parallel treatment groups: structured sleep hygiene, structured sleep hygiene with late afternoon moderate exercise, and structured sleep hygiene with early morning light therapy. Patients responded to questionnaires and filled out sleep logs. In addition, they underwent clinical evaluation, structured interviews, nocturnal monitoring, and actigraphy. The analyzed variables before and at the end of treatment were those derived from sleep logs and actigraphy.
RESULTS: All subjects showed a trend toward improvement, independent of the treatment received, but only the "structured sleep hygiene with light treatment" showed statistically significant improvement at the end of the trial.
CONCLUSIONS: Patients with chronic psychophysiologic insomnia may benefit from a nondrug treatment approach. Light therapy appears particularly promising.
Nina Buscemi, Ben Vandermeer, Carol Friesen, Liza Bialy, Michelle Tubman, Maria Ospina, Terry P Klassen, Manisha Witmans
The efficacy and safety of drug treatments for chronic insomnia in adults: a meta-analysis of RCTs.
J Gen Intern Med. 2007 Sep;22(9):1335-50. doi: 10.1007/s11606-007-0251-z. Epub 2007 Jul 10.
Abstract/Text
BACKGROUND: Hypnotics have a role in the management of acute insomnia; however, the efficacy and safety of pharmacological interventions in the management of chronic insomnia is unclear.
OBJECTIVE: The objective of this paper is to conduct a systematic review of the efficacy and safety of drug treatments for chronic insomnia in adults.
DATA SOURCES: Twenty-one electronic databases were searched, up to July 2006.
STUDY SELECTION: Randomized double-blind, placebo-controlled trials were eligible. Quality was assessed using the Jadad scale. Data were pooled using the random effects model.
DATA SYNTHESIS: One hundred and five studies were included in the review. Sleep onset latency, as measured by polysomnography, was significantly decreased for benzodiazepines (BDZ), (weighted mean difference: -10.0 minutes; 95% CI: -16.6, -3.4), non-benzodiazepines (non-BDZ) (-12.8 minutes; 95% CI: -16.9, -8.8) and antidepressants (ADP) (-7.0 minutes; 95% CI: -10.7, -3.3). Sleep onset latency assessed by sleep diaries was also improved (BDZ: -19.6 minutes; 95% CI: -23.9, -15.3; non-BDZ: -17.0 minutes; 95% CI: -20.0, -14.0; ADP: -12.2 minutes; 95% CI: -22.3, -2.2). Indirect comparisons between drug categories suggest BDZ and non-BDZ have a similar effect. All drug groups had a statistically significant higher risk of harm compared to placebo (BDZ: risk difference [RD]: 0.15; non-BDZ RD: 0.07; and ADP RD: 0.09), although the most commonly reported adverse events were minor. Indirect comparisons suggest that non-BDZ are safer than BDZ.
CONCLUSIONS: Benzodiazepines and non-benzodiazepines are effective treatments in the management of chronic insomnia, although they pose a risk of harm. There is also some evidence that antidepressants are effective and that they pose a risk of harm.
A M Holbrook, R Crowther, A Lotter, C Cheng, D King
Meta-analysis of benzodiazepine use in the treatment of insomnia.
CMAJ. 2000 Jan 25;162(2):225-33.
Abstract/Text
OBJECTIVE: To systematically review the benefits and risks associated with the use of benzodiazepines to treat insomnia in adults.
DATA SOURCES: MEDLINE and the Cochrane Controlled Trials Registry were searched for English-language articles published from 1966 to December 1998 that described randomized controlled trials of benzodiazepines for the treatment of insomnia. Key words included "benzodiazepines" (exploded), "randomized controlled trial" and "insomnia." Bibliographies of relevant articles were reviewed for additional studies and manufacturers of benzodiazepines were asked to submit additional randomized controlled trial reports not in the literature.
STUDY SELECTION: Articles were considered for the meta-analysis if they were randomized controlled trials involving patients with insomnia and compared a benzodiazepine with placebo or another active agent. Of the 89 trials originally identified, 45 met our criteria, representing a total of 2672 patients.
DATA EXTRACTION: Data were extracted regarding the participants, the setting, details of the intervention, the outcomes (including adverse effects) and the methodologic quality of the studies.
DATA SYNTHESIS: The meta-analyses of sleep records indicated that, when compared with placebo, benzodiazepines decreased sleep latency by 4.2 minutes (non-significant; 95% confidence interval (CI -0.7 to 9.2) and significantly increased total sleep duration by 61.8 minutes (95% CI 37.4 to 86.2). Patient-reported outcomes were more optimistic for sleep latency; those randomized to benzodiazepine treatment estimated a sleep latency decrease of 14.3 minutes (95% CI 10.6 to 18.0). Although more patients receiving benzodiazepine treatment reported adverse effects, especially daytime drowsiness and dizziness or light-headedness (common odds ratio 1.8, 95% CI 1.4 to 2.4), dropout rates for the benzodiazepine and placebo groups were similar. Cognitive function decline including memory impairment was reported in several of the studies. Zopiclone was not found to be superior to benzodiazepines on any of the outcome measures examined.
INTERPRETATION: The use of benzodiazepines in the treatment of insomnia is associated with an increase in sleep duration, but this is countered by a number of adverse effects. Additional studies evaluating the efficacy of nonpharmacological interventions would be valuable.
P D Nowell, S Mazumdar, D J Buysse, M A Dew, C F Reynolds, D J Kupfer
Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy.
JAMA. 1997 Dec 24-31;278(24):2170-7.
Abstract/Text
OBJECTIVE: To evaluate the efficacy of benzodiazepines and zolpidem tartrate in chronic insomnia based on a quantitative review of literature.
DATA SOURCES: Articles from 1966 to 1996 were identified using MEDLINE, by a manual review of relevant journals, and from bibliographies of identified articles.
STUDY SELECTION: Studies using randomized, double-blind, placebo-controlled, parallel or crossover designs with benzodiazepines or zolpidem in adults younger than 65 years with chronic insomnia (modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for primary insomnia) were selected for review. Self-report and polysomnographic measures of sleep-onset latency, total sleep time, number of awakenings, and sleep quality were selected as outcomes.
DATA EXTRACTION: Twenty-two studies met the selection criteria. A combined test of Pvalues was performed, pooling broadly from the 22 studies to determine whether medication was superior to placebo. A combined test of effect sizes was performed on the subset of studies that reported effect size information to determine the magnitude of medication effect.
DATA SYNTHESIS: A homogeneous sample of studies summarized 1894 patients treated for a median duration of 7 days. The combined test of P values demonstrated that medication was superior to placebo in all 4 outcome measures. Treatment response was moderate in magnitude by the combined test of effect sizes.
CONCLUSIONS: Benzodiazepines and zolpidem produced reliable improvements in commonly measured parameters of sleep in patients with chronic insomnia. Relative to the chronic and recurring course of insomnia, both the limited duration of treatments studied and the lack of follow-up data from controlled trials represent challenges for developing evidence-based guidelines for the use of hypnotics in the management of chronic insomnia.
Andrew D Krystal
A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: the empirical basis for U.S. clinical practice.
Sleep Med Rev. 2009 Aug;13(4):265-74. doi: 10.1016/j.smrv.2008.08.001. Epub 2009 Jan 18.
Abstract/Text
For many years practitioners have had limited data from double-blind, placebo-controlled studies to guide the types of decision-making needed to optimally manage patients with insomnia in clinical practice. However, in recent years there has been a great increase in insomnia research studies that address issues of clinical importance. This body of work represents an increasingly useful empirical basis for making clinical practice decisions. The purpose of this article is to compile the body of work on the pharmacological management of insomnia to make it available in as accessible form as possible for optimal application in clinical practice with the hopes that doing so will decrease the gap separating the available research and the clinical management of insomnia and, thereby, improve the care of the many individuals who suffer from this condition. The review of studies consists of the following sections: 1) basic pharmacology; 2) double-blind, placebo-controlled trials in adults with primary insomnia; 3) double-blind, placebo-controlled trials in elderly patients with primary insomnia; 4) adverse effects reported in placebo-controlled trials in elderly primary insomnia patients; 5) double-blind, placebo-controlled trials in adults and the elderly as a function of treatment duration; 6) double-blind, placebo-controlled trials of the treatment of comorbid insomnia. Issues related to the application of these data to clinical practice are discussed in the text.
F Verdon, B Burnand, C-L Fallab Stubi, C Bonard, M Graff, A Michaud, T Bischoff, M de Vevey, J-P Studer, L Herzig, C Chapuis, J Tissot, A Pécoud, B Favrat
Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial.
BMJ. 2003 May 24;326(7399):1124. doi: 10.1136/bmj.326.7399.1124.
Abstract/Text
OBJECTIVE: To determine the subjective response to iron therapy in non-anaemic women with unexplained fatigue.
DESIGN: Double blind randomised placebo controlled trial.
SETTING: Academic primary care centre and eight general practices in western Switzerland.
PARTICIPANTS: 144 women aged 18 to 55, assigned to either oral ferrous sulphate (80 mg/day of elemental iron daily; n=75) or placebo (n=69) for four weeks.
MAIN OUTCOME MEASURES: Level of fatigue, measured by a 10 point visual analogue scale.
RESULTS: 136 (94%) women completed the study. Most had a low serum ferritin concentration; CONCLUSION: Non-anaemic women with unexplained fatigue may benefit from iron supplementation. The effect may be restricted to women with low or borderline serum ferritin concentrations.
Pierre-Alexandre Krayenbuehl, Edouard Battegay, Christian Breymann, Joerg Furrer, Georg Schulthess
Intravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentration.
Blood. 2011 Sep 22;118(12):3222-7. doi: 10.1182/blood-2011-04-346304. Epub 2011 Jun 24.
Abstract/Text
This is the first study to investigate the efficacy of intravenous iron in treating fatigue in nonanemic patients with low serum ferritin concentration. In a randomized, double-blinded, placebo-controlled study, 90 premenopausal women presenting with fatigue, serum ferritin ≤ 50 ng/mL, and hemoglobin ≥ 120 g/L were randomized to receive either 800 mg of intravenous iron (III)-hydroxide sucrose or intravenous placebo. Fatigue and serum iron status were assessed at baseline and after 6 and 12 weeks. Median fatigue at baseline was 4.5 (on a 0-10 scale). Fatigue decreased during the initial 6 weeks by 1.1 in the iron group compared with 0.7 in the placebo group (P = .07). Efficacy of iron was bound to depleted iron stores: In patients with baseline serum ferritin ≤ 15 ng/mL, fatigue decreased by 1.8 in the iron group compared with 0.4 in the placebo group (P = .005), and 82% of iron-treated compared with 47% of placebo-treated patients reported improved fatigue (P = .03). Drug-associated adverse events were observed in 21% of iron-treated patients and in 7% of placebo-treated patients (P = .05); none of these events was serious. Intravenous administration of iron improved fatigue in iron-deficient, nonanemic women with a good safety and tolerability profile. The efficacy of intravenous iron was bound to a serum ferritin concentration ≤ 15 ng/mL. This study was registered at the International Standard Randomized Controlled Trial Number Register (www.isrctn.org) as ISRCTN78430425.
Ruchika Sharma, Joseph R Stanek, Terah L Koch, Linda Grooms, Sarah H O'Brien
Intravenous iron therapy in non-anemic iron-deficient menstruating adolescent females with fatigue.
Am J Hematol. 2016 Oct;91(10):973-7. doi: 10.1002/ajh.24461. Epub 2016 Jul 20.
Abstract/Text
Menstruating women, with or without underlying bleeding disorders, are at increased risk for developing iron deficiency-related fatigue, even in the absence of anemia. Oral iron therapy has limitations which include poor absorption and non-adherence due to gastrointestinal side effects. We performed a prospective clinical trial of post-menarchal adolescent females with iron-deficiency with or without mild anemia and fatigue who received a standardized regimen of intravenous iron sucrose. The baseline mean (SD) hemoglobin was 11.96 g dl(-1) (1.05) in 20 girls (ages 14-21 years); with a range of 10.3-14.1 g dl(-1) . In this cohort, intravenous iron was well tolerated and patients demonstrated a sustained increase in ferritin levels with means (SD) of 13.4 ng ml(-1) (13.1) at baseline to 141.5 ng ml(-1) (104.5) at 6 weeks and 85.2 ng ml(-1) (128.4) at 6 months after the infusions. We used a standardized (Peds QL(TM) Multidimensional) fatigue scale to objectively measure fatigue and proxy scores by parents with mean screening scores (SD) of 35.2 (16.8) and 31.9 (19.6), respectively. We demonstrated a clinically significant improvement both in patient as well as parent fatigue scores (in 19 out of 20 subjects) at 6 weeks (Mean (SD) 58.3 (21.3) [P < 0.0001] and 57 (24.4) [P < 0.0001], respectively); as well as 3 and 6 months after the iron infusions. In nonanemic patients, iron administration did not significantly influence hemoglobin concentration. Therefore, the fatigue-reducing effects of iron therapy reflect the nonhematological functions of iron. Am. J. Hematol. 91:973-977, 2016. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.
Marcus J H Huibers, Anna J H M Beurskens, Constant P Van Schayck, Ellen Bazelmans, Job F M Metsemakers, J Andre Knottnerus, Gijs Bleijenberg
Efficacy of cognitive-behavioural therapy by general practitioners for unexplained fatigue among employees: Randomised controlled trial.
Br J Psychiatry. 2004 Mar;184:240-6.
Abstract/Text
BACKGROUND: Fatigue is a common complaint that may lead to long-term sick leave and work disability.
AIMS: To assess the efficacy of cognitive-behavioural therapy by general practitioners for unexplained, persistent fatigue among employees.
METHOD: A randomised controlled trial, using a pre-randomisation design in primary care, investigated 151 employees on sick leave with fatigue. Participants in the experimental group were offered five to seven 30 min sessions of cognitive-behavioural therapy by a general practitioner; those in the control group were offered no treatment. Main outcome measures (fatigue severity, self-reported absenteeism, registered absenteeism and clinical recovery) were assessed at 4 months, 8 months and 12 months.
RESULTS: At baseline, 44% of the patients already met research criteria for chronic fatigue syndrome. There was no significant difference between the experimental group and the control group on primary or secondary outcomes at any point.
CONCLUSIONS: Cognitive-behavioural therapy by general practitioners for unexplained, persistent fatigue did not prove to be an effective intervention. Since these doctors were unable to deliver this therapy effectively under ideal circumstances, it is unlikely that doctors in routine practice would be more successful in doing so.
J R Price, J Couper
Cognitive behaviour therapy for adults with chronic fatigue syndrome.
Cochrane Database Syst Rev. 2000;(2):CD001027. doi: 10.1002/14651858.CD001027.
Abstract/Text
OBJECTIVES: 1. To systematically review all randomised controlled trials of cognitive-behaviour therapy (CBT) for adults with chronic fatigue syndrome (CFS); 2. To test the hypothesis that CBT is more effective than orthodox medical management or other interventions in adults with CFS.
SEARCH STRATEGY: 1. Electronic searching of bibliographic databases, including Medline, PsycLIT, Biological Abstracts, Embase, SIGLE, Index to Theses, Index to Scientific and Technical Proceedings, and Science Citation Index, using multiple search terms in order to perform a highly sensitive search. 2. Electronic searching of the Trials Register of the Depression, Anxiety and Neurosis group. 3. Citation lists of relevant studies and reviews were perused for other relevant trials. 4. Contact with the principal authors of relevant studies, and with researchers in the field.
SELECTION CRITERIA: All randomised controlled trials were included in which - adult patients with CFS; - received CBT or a control intervention, being either orthodox medical management or another intervention; - and whose outcomes were assessed in an appropriate way. CBT could be either type 'A' (encouraging return to 'normal' levels of rest and activity) or type 'B' (encouraging rest and activity which were within levels imposed by the disorder).
DATA COLLECTION AND ANALYSIS: The two reviewers worked independently throughout the selection of trials and data extraction, comparing findings only when there was disagreement. Relevant trials were allocated to one of three quality categories. Full data extraction, using a standardised data extraction sheet, was performed on studies which were of high or moderate quality. Trials of low quality were excluded from the review. The comparisons made to test the review hypothesis were of type 'A' CBT versus other intervention(s), and of type 'B' CBT versus other intervention(s). Functional outcome was used as the main outcome for comparison, but other appropriate outcomes were compared where possible. Results were synthesised using the Review Manager software. For dichotomous data, the odds ratio was calculated for each study. For continuous data, effect sizes were obtained and the standardised mean difference, with 95% confidence intervals, was calculated.
MAIN RESULTS: Only three relevant trials of adequate quality were found. These trials demonstrated that CBT significantly benefits physical functioning in adult out-patients with CFS when compared to orthodox medical management or relaxation. It is necessary to treat about two patients to prevent one additional unsatisfactory physical outcome about six months after treatment end. CBT appeared highly acceptable to the patients in these trials. There is no satisfactory evidence for the effectiveness of CBT in patients with the milder forms of CFS found in primary care or in patients who are so disabled that they are unable to attend out-patients. Additionally, there is no satisfactory evidence for the effectiveness of group CBT.
REVIEWER'S CONCLUSIONS: Cognitive behaviour therapy appears to be an effective and acceptable treatment for adult out-patients with chronic fatigue syndrome. CFS is a common and disabling disorder. Its sufferers deserve the medical profession to be more aware of the potential of this therapy to bring lasting functional benefit, and health service managers to increase its availability. Further research is needed in this important area. Trials should conform to accepted standards of reporting and methodology. The effectiveness of CBT in more and less severely disabled patients than those usually seen in out-patient clinics needs to be assessed. Trials of group CBT and in-patient CBT compared to orthodox medical management, and of CBT compared to graded activity alone, also need to be conducted.
Judith B Prins, Jos W M van der Meer, Gijs Bleijenberg
Chronic fatigue syndrome.
Lancet. 2006 Jan 28;367(9507):346-55. doi: 10.1016/S0140-6736(06)68073-2.
Abstract/Text
During the past two decades, there has been heated debate about chronic fatigue syndrome (CFS) among researchers, practitioners, and patients. Few illnesses have been discussed so extensively. The existence of the disorder has been questioned, its underlying pathophysiology debated, and an effective treatment opposed; patients' organisations have participated in scientific discussions. In this review, we look back on several controversies over CFS with respect to its definition, diagnosis, pathophysiology, and treatment. We review issues of epidemiology and clinical manifestations, focusing on the scientific status of CFS. Modern neuroscience and genetics research offer interesting findings for new hypotheses on the aetiology and pathogenesis of the illness. We also discuss promising future issues, such as psychopathophysiology and mechanisms of improvement, and suggest multidisciplinary prospective studies of CFS and fatigue in the general population. These studies should pay particular attention to similarities to and differences from functional somatic syndromes and other fatiguing conditions.
L Ridsdale, L Darbishire, P T Seed
Is graded exercise better than cognitive behaviour therapy for fatigue? A UK randomized trial in primary care.
Psychol Med. 2004 Jan;34(1):37-49.
Abstract/Text
BACKGROUND: Patients frequently present with unexplained fatigue in primary care, but there have been few treatment trials in this context. We aimed to test cognitive behaviour therapy (CBT) and graded exercise therapy (GET) for patients presenting to their family doctor with fatigue. Secondly, we described the outcome for a cohort of patients who presented to the same doctors with fatigue, who received standard care, plus a booklet.
METHOD: This was a randomized trial, followed by a prospective cohort study. Twenty-two practices in SE England referred 144 patients aged 16 to 75 years with over 3 months of unexplained fatigue. Self-rated fatigue score, the hospital anxiety and depression rating scale, functional impairment, physical step-test performance and causal attributions were measured. In the trial six sessions of CBT or GET were randomly allocated.
RESULTS: In the therapy groups the mean fatigue score decreased by 10 points (95% confidence interval (CI) = -25 to -15), with no significant difference between groups (mean difference = -1.3; CI = -3.9 to 1.3). Fewer patients attended for GET. At outcome one-half of patients had clinically important fatigue in both randomized groups, but patients in the group offered CBT were less anxious. Twenty-seven per cent of the patients met criteria for CFS at baseline. Only 25% of this subgroup recovered, compared to 60% of the subgroup that did not meet criteria for CFS.
CONCLUSIONS: Short courses of GET were not superior to CBT for patients consulting with fatigue of over 3 months in primary care. CBT was easier 'to sell'. Low recovery in the CFS subgroup suggests that brief treatment is too short.
I M Okkes, S K Oskam, H Lamberts
The probability of specific diagnoses for patients presenting with common symptoms to Dutch family physicians.
J Fam Pract. 2002 Jan;51(1):31-6.
Abstract/Text
OBJECTIVE: Our goal was to develop reliable data on the probability of specific diagnoses among patients of family physicians (FPs) presenting with common symptoms.
STUDY DESIGN: A group of 54 Dutch FPs recorded the reasons for encounter, diagnoses, and interventions for all episodes of care between 1985 and 1995. Diagnoses could be modified during the episode of care, and a modified diagnosis was applied to all episode data.
POPULATION: We used the listed patient populations of the 54 Dutch FPs, representing 93,297 patient years, 236,027 episodes of care, and 267,897 patient encounters.
OUTCOMES MEASURED: The top 20 diagnoses related to 4 selected presenting symptoms (cough, shortness of breath, general weakness/tiredness, and low back symptom/complaints without radiation), per 100 patients, with 95% confidence intervals, stratified by age. In the standard tables, age-specific cells with fewer than 10 observations were excluded.
RESULTS: The availability of an accurate estimate of prior (pretest) probabilities for common symptoms/complaints has great potential value for family practice as an academic discipline and for family physicians in that it can support their medical decision making. Stratifying data by age groups increases the clinical relevance of the prior probabilities.
CONCLUSIONS: Though collected by Dutch FPs, the data in our study have a high face validity for other clinicians. Still, FPs in other countries should give priority to collecting their own probability databases.
D W Bates, W Schmitt, D Buchwald, N C Ware, J Lee, E Thoyer, R J Kornish, A L Komaroff
Prevalence of fatigue and chronic fatigue syndrome in a primary care practice.
Arch Intern Med. 1993 Dec 27;153(24):2759-65.
Abstract/Text
BACKGROUND: Our goals were to determine the prevalence of unusual, debilitating fatigue and the frequency with which it was associated with the chronic fatigue syndrome (CFS) or other physical or psychological illness in an outpatient clinic population.
METHODS: We prospectively evaluated a cohort of 1000 consecutive patients in a primary care clinic in an urban, hospital-based general medicine practice. The study protocol included a detailed history, physical examination, and laboratory and psychiatric testing.
RESULTS: Five patients who came because of CFS studies were excluded. Of the remaining 995, 323 reported fatigue, and 271 (27%) complained of at least 6 months of unusual fatigue that interfered with their daily lives. Of the 271, self-report or record review revealed a medical or psychiatric condition that could have explained the fatigue in 186 (69%). Thus, 85 (8.5%) of 995 patients had a debilitating fatigue of at least 6 months' duration, without apparent cause. Of these patients, 48 refused further evaluation, and 11 were unavailable for follow-up; 26 completed the protocol. Three of the 26 were hypothyroid, and one had a major psychiatric disorder. Of the remaining 22 patients, three met Centers for Disease Control and Prevention criteria for CFS, four met British criteria, and 10 met the Australian case definition. The point prevalences of CFS were thus 0.3% (95% confidence interval [CI], 0% to 0.6%), 0.4% (95% CI, 0% to 0.8%), and 1.0% (95% CI, 0.4% to 1.6%) using the Centers for Disease Control and Prevention, British, and Australian case definitions, respectively. These estimates were conservative, because they assumed that none of the patients who refused evaluation or were unavailable for follow-up would meet criteria for CFS.
CONCLUSIONS: While chronic, debilitating fatigue is common in medical outpatients, CFS is relatively uncommon. Prevalence depends substantially on the case definition used.
F Conti, R Priori, G De Petrillo, A C Rusconi, C Arpino, G Valesini
Prevalence of chronic fatigue syndrome in Italian patients with persistent fatigue.
Ann Ital Med Int. 1994 Oct-Dec;9(4):219-22.
Abstract/Text
Our study was carried out to determine the prevalence of chronic fatigue syndrome (CFS) within a selected population of patients suffering from persistent fatigue. We studied subjects with recurrent or persistent fatigue lasting 6 months and fulfilling at least four minor Center for Disease Control (CDC) criteria for the diagnosis of CFS. Evaluation included both clinical examination and laboratory testing. All subjects filled out a questionnaire specifically designed to gain information about the length and severity of symptoms, and patients with a previously diagnosed illness associated with fatigue were excluded. The study was carried out at the Fatigue Clinic of an internal medicine unit (Clinica Medica I) of the University of Rome "La Sapienza". Sixty-three subjects, residents of the Lazio region (central Italy), completed the diagnostic assessment. Alternative diagnoses were established in 37 (59%) of the 63 patients. A diagnosis of CFS based on the CDC criteria was established in only 6 cases. In 2 subjects, CFS had appeared following infectious mononucleosis, and no definitive diagnosis could be formulated for 18 patients. In Italy, CFS seems to be an infrequent cause of severe and persistent fatigue in a selected population. Numerous morbid conditions may be responsible for a clinical picture closely resembling CFS. We recommend that patients suffering from fatigue be thoroughly evaluated.
L Ridsdale, A Evans, W Jerrett, S Mandalia, K Osler, H Vora
Patients with fatigue in general practice: a prospective study.
BMJ. 1993 Jul 10;307(6896):103-6.
Abstract/Text
OBJECTIVE: To describe the characteristics of patients attending their general practitioners and complaining of fatigue or being "tired all the time."
DESIGN: Prospective study of cohort aged 16 years and older with follow up at two weeks and by questionnaires at two and six months.
SUBJECTS: 220 patients (164 women) with mean age 43 years and an age-sex matched comparison group.
SETTINGS: Doctors and patients in four practices in Lancashire, Mid Glamorgan, Suffolk, and Surrey.
MAIN OUTCOME MEASURES: General clinical data, results from standard group of laboratory tests, fatigue questionnaire, and 12 item general health questionnaire.
RESULTS: Over twice as many patients with fatigue had high scores on the health questionnaire compared with the comparison group (156 (75%) v 69 (34%)). Results of laboratory tests were abnormal and contributed to the diagnosis in 19 patients. 59 out of 102 patients who responded had high fatigue scores six months later. Patients with persistent fatigue were more likely to have a history of anxiety or depression and to have had fatigue for more than three months on entry to the study.
CONCLUSIONS: Women are particularly at risk of fatigue. The outcome is better if patients have had symptoms for three months or less or there is no history of emotional illness.
Jennifer Wright, Kim M O'Connor
Fatigue.
Med Clin North Am. 2014 May;98(3):597-608. doi: 10.1016/j.mcna.2014.01.010.
Abstract/Text
Fatigue is a common symptom in primary care with many causes ranging from benign to life threatening. Appropriate evaluation and management are guided by the patient's history, which provides valuable clues as to the source of the patient's symptoms. Ultimately a diagnosis may not be identified for many patients presenting with fatigue, and in these patients management is the most challenging. This article offers guidance in the management of patients presenting with fatigue including key aspects of the patient's history of present illness, the building of a differential diagnosis, rational evaluation in a patient with a nondiagnostic history, and management in the setting of a nondiagnostic work-up.
Copyright © 2014 Elsevier Inc. All rights reserved.
Alexandra Rolfe, Christopher Burton
Reassurance after diagnostic testing with a low pretest probability of serious disease: systematic review and meta-analysis.
JAMA Intern Med. 2013 Mar 25;173(6):407-16. doi: 10.1001/jamainternmed.2013.2762.
Abstract/Text
IMPORTANCE: Diagnostic tests are often ordered by physicians in patients with a low pretest probability of disease to rule out conditions and reassure the patient.
OBJECTIVE: To study the effect of diagnostic tests on worry about illness, anxiety, symptom persistence, and subsequent use of health care resources in patients with a low pretest probability of serious illness.
EVIDENCE ACQUISITION: Systematic review and meta-analysis. We searched MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, PsychINFO, CINAHL, and ProQuest Dissertations electronic databases through December 31, 2011, for eligible randomized controlled trials. We independently identified studies for inclusion and extracted the data. Disagreements were resolved by discussion. We performed meta-analysis if heterogeneity was low or moderate (I2 < 50%).
RESULTS: Fourteen randomized controlled trials that included 3828 patients met the inclusion criteria and were analyzed with outcomes categorized as short term (≤3 months) or long term (>3 months). Three trials showed no overall effect of diagnostic tests on illness worry (odds ratio, 0.87 [95% CI, 0.55-1.39]), and 2 showed no effect on nonspecific anxiety (standardized mean difference, 0.06 [-0.16 to 0.28]). Ten trials showed no overall long-term effect on symptom persistence (odds ratio, 0.99 [95% CI, 0.85-1.15]). Eleven trials measured subsequent primary care visits. We observed a high level of heterogeneity among trials (I2 = 80%). Meta-analysis after exclusion of outliers suggested a small reduction in visits after investigation (odds ratio, 0.77 [95% CI, 0.62-0.96]).
CONCLUSIONS AND RELEVANCE: Diagnostic tests for symptoms with a low risk of serious illness do little to reassure patients, decrease their anxiety, or resolve their symptoms, although the tests may reduce further primary care visits. Further research is needed to maximize reassurance from medically necessary tests and to develop safe strategies for managing patients without testing when an abnormal result is unlikely.
Angelo Carfì, Roberto Bernabei, Francesco Landi, Gemelli Against COVID-19 Post-Acute Care Study Group
Persistent Symptoms in Patients After Acute COVID-19.
JAMA. 2020 Aug 11;324(6):603-605. doi: 10.1001/jama.2020.12603.
Abstract/Text
Mark W Tenforde, Sara S Kim, Christopher J Lindsell, Erica Billig Rose, Nathan I Shapiro, D Clark Files, Kevin W Gibbs, Heidi L Erickson, Jay S Steingrub, Howard A Smithline, Michelle N Gong, Michael S Aboodi, Matthew C Exline, Daniel J Henning, Jennifer G Wilson, Akram Khan, Nida Qadir, Samuel M Brown, Ithan D Peltan, Todd W Rice, David N Hager, Adit A Ginde, William B Stubblefield, Manish M Patel, Wesley H Self, Leora R Feldstein, IVY Network Investigators, CDC COVID-19 Response Team, IVY Network Investigators
Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network - United States, March-June 2020.
MMWR Morb Mortal Wkly Rep. 2020 Jul 31;69(30):993-998. doi: 10.15585/mmwr.mm6930e1. Epub 2020 Jul 31.
Abstract/Text
Prolonged symptom duration and disability are common in adults hospitalized with severe coronavirus disease 2019 (COVID-19). Characterizing return to baseline health among outpatients with milder COVID-19 illness is important for understanding the full spectrum of COVID-19-associated illness and tailoring public health messaging, interventions, and policy. During April 15-June 25, 2020, telephone interviews were conducted with a random sample of adults aged ≥18 years who had a first positive reverse transcription-polymerase chain reaction (RT-PCR) test for SARS-CoV-2, the virus that causes COVID-19, at an outpatient visit at one of 14 U.S. academic health care systems in 13 states. Interviews were conducted 14-21 days after the test date. Respondents were asked about demographic characteristics, baseline chronic medical conditions, symptoms present at the time of testing, whether those symptoms had resolved by the interview date, and whether they had returned to their usual state of health at the time of interview. Among 292 respondents, 94% (274) reported experiencing one or more symptoms at the time of testing; 35% of these symptomatic respondents reported not having returned to their usual state of health by the date of the interview (median = 16 days from testing date), including 26% among those aged 18-34 years, 32% among those aged 35-49 years, and 47% among those aged ≥50 years. Among respondents reporting cough, fatigue, or shortness of breath at the time of testing, 43%, 35%, and 29%, respectively, continued to experience these symptoms at the time of the interview. These findings indicate that COVID-19 can result in prolonged illness even among persons with milder outpatient illness, including young adults. Effective public health messaging targeting these groups is warranted. Preventative measures, including social distancing, frequent handwashing, and the consistent and correct use of face coverings in public, should be strongly encouraged to slow the spread of SARS-CoV-2.
Oscar Moreno-Pérez, Esperanza Merino, Jose-Manuel Leon-Ramirez, Mariano Andres, Jose Manuel Ramos, Juan Arenas-Jiménez, Santos Asensio, Rosa Sanchez, Paloma Ruiz-Torregrosa, Irene Galan, Alexander Scholz, Antonio Amo, Pilar González-delaAleja, Vicente Boix, Joan Gil, COVID19-ALC research group
Post-acute COVID-19 Syndrome. Incidence and risk factors: a Mediterranean cohort study.
J Infect. 2021 Jan 12;. doi: 10.1016/j.jinf.2021.01.004. Epub 2021 Jan 12.
Abstract/Text
OBJECTIVES: This study aims to analyze the incidence of Post-acute COVID-19 syndrome (PCS) and its components, and to evaluate the acute infection phase associated risk factors.
METHODS: A prospective cohort study of adult patients who had recovered from COVID-19 (27th February to 29th April 2020) confirmed by PCR or subsequent seroconversion, with a systematic assessment 10-14 weeks after disease onset. PCS was defined as the persistence of at least one clinically relevant symptom, or abnormalities in spirometry or chest radiology. Outcome predictors were analyzed by multiple logistic regression (OR; 95%CI).
RESULTS: Two hundred seventy seven patients recovered from mild (34.3%) or severe (65.7%) forms of SARS-CoV-2 infection were evaluated 77 days (IQR 72-85) after disease onset. PCS was detected in 141 patients (50.9%; 95%CI 45.0-56.7%). Symptoms were mostly mild. Alterations in spirometry were noted in 25/269 (9.3%), while in radiographs in 51/277 (18.9%). No baseline clinical features behaved as independent predictors of PCS development.
CONCLUSIONS: A Post-acute COVID-19 syndrome was detected in a half of COVID19 survivors. Radiological and spirometric changes were mild and observed in less than 25% of patients. No baseline clinical features behaved as independent predictors of Post-acute COVID-19 syndrome development.
Copyright © 2021. Published by Elsevier Ltd.
Liam Townsend, Adam H Dyer, Karen Jones, Jean Dunne, Aoife Mooney, Fiona Gaffney, Laura O'Connor, Deirdre Leavy, Kate O'Brien, Joanne Dowds, Jamie A Sugrue, David Hopkins, Ignacio Martin-Loeches, Cliona Ni Cheallaigh, Parthiban Nadarajan, Anne Marie McLaughlin, Nollaig M Bourke, Colm Bergin, Cliona O'Farrelly, Ciaran Bannan, Niall Conlon
Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection.
PLoS One. 2020;15(11):e0240784. doi: 10.1371/journal.pone.0240784. Epub 2020 Nov 9.
Abstract/Text
Fatigue is a common symptom in those presenting with symptomatic COVID-19 infection. However, it is unknown if COVID-19 results in persistent fatigue in those recovered from acute infection. We examined the prevalence of fatigue in individuals recovered from the acute phase of COVID-19 illness using the Chalder Fatigue Score (CFQ-11). We further examined potential predictors of fatigue following COVID-19 infection, evaluating indicators of COVID-19 severity, markers of peripheral immune activation and circulating pro-inflammatory cytokines. Of 128 participants (49.5 ± 15 years; 54% female), more than half reported persistent fatigue (67/128; 52.3%) at median of 10 weeks after initial COVID-19 symptoms. There was no association between COVID-19 severity (need for inpatient admission, supplemental oxygen or critical care) and fatigue following COVID-19. Additionally, there was no association between routine laboratory markers of inflammation and cell turnover (leukocyte, neutrophil or lymphocyte counts, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, C-reactive protein) or pro-inflammatory molecules (IL-6 or sCD25) and fatigue post COVID-19. Female gender and those with a pre-existing diagnosis of depression/anxiety were over-represented in those with fatigue. Our findings demonstrate a significant burden of post-viral fatigue in individuals with previous SARS-CoV-2 infection after the acute phase of COVID-19 illness. This study highlights the importance of assessing those recovering from COVID-19 for symptoms of severe fatigue, irrespective of severity of initial illness, and may identify a group worthy of further study and early intervention.
Chaolin Huang, Lixue Huang, Yeming Wang, Xia Li, Lili Ren, Xiaoying Gu, Liang Kang, Li Guo, Min Liu, Xing Zhou, Jianfeng Luo, Zhenghui Huang, Shengjin Tu, Yue Zhao, Li Chen, Decui Xu, Yanping Li, Caihong Li, Lu Peng, Yong Li, Wuxiang Xie, Dan Cui, Lianhan Shang, Guohui Fan, Jiuyang Xu, Geng Wang, Ying Wang, Jingchuan Zhong, Chen Wang, Jianwei Wang, Dingyu Zhang, Bin Cao
6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.
Lancet. 2021 Jan 16;397(10270):220-232. doi: 10.1016/S0140-6736(20)32656-8. Epub 2021 Jan 8.
Abstract/Text
BACKGROUND: The long-term health consequences of COVID-19 remain largely unclear. The aim of this study was to describe the long-term health consequences of patients with COVID-19 who have been discharged from hospital and investigate the associated risk factors, in particular disease severity.
METHODS: We did an ambidirectional cohort study of patients with confirmed COVID-19 who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7, 2020, and May 29, 2020. Patients who died before follow-up, patients for whom follow-up would be difficult because of psychotic disorders, dementia, or re-admission to hospital, those who were unable to move freely due to concomitant osteoarthropathy or immobile before or after discharge due to diseases such as stroke or pulmonary embolism, those who declined to participate, those who could not be contacted, and those living outside of Wuhan or in nursing or welfare homes were all excluded. All patients were interviewed with a series of questionnaires for evaluation of symptoms and health-related quality of life, underwent physical examinations and a 6-min walking test, and received blood tests. A stratified sampling procedure was used to sample patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5-6, to receive pulmonary function test, high resolution CT of the chest, and ultrasonography. Enrolled patients who had participated in the Lopinavir Trial for Suppression of SARS-CoV-2 in China received severe acute respiratory syndrome coronavirus 2 antibody tests. Multivariable adjusted linear or logistic regression models were used to evaluate the association between disease severity and long-term health consequences.
FINDINGS: In total, 1733 of 2469 discharged patients with COVID-19 were enrolled after 736 were excluded. Patients had a median age of 57·0 (IQR 47·0-65·0) years and 897 (52%) were men. The follow-up study was done from June 16, to Sept 3, 2020, and the median follow-up time after symptom onset was 186·0 (175·0-199·0) days. Fatigue or muscle weakness (63%, 1038 of 1655) and sleep difficulties (26%, 437 of 1655) were the most common symptoms. Anxiety or depression was reported among 23% (367 of 1617) of patients. The proportions of median 6-min walking distance less than the lower limit of the normal range were 24% for those at severity scale 3, 22% for severity scale 4, and 29% for severity scale 5-6. The corresponding proportions of patients with diffusion impairment were 22% for severity scale 3, 29% for scale 4, and 56% for scale 5-6, and median CT scores were 3·0 (IQR 2·0-5·0) for severity scale 3, 4·0 (3·0-5·0) for scale 4, and 5·0 (4·0-6·0) for scale 5-6. After multivariable adjustment, patients showed an odds ratio (OR) 1·61 (95% CI 0·80-3·25) for scale 4 versus scale 3 and 4·60 (1·85-11·48) for scale 5-6 versus scale 3 for diffusion impairment; OR 0·88 (0·66-1·17) for scale 4 versus scale 3 and OR 1·77 (1·05-2·97) for scale 5-6 versus scale 3 for anxiety or depression, and OR 0·74 (0·58-0·96) for scale 4 versus scale 3 and 2·69 (1·46-4·96) for scale 5-6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1·73 m2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m2 at follow-up.
INTERPRETATION: At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression. Patients who were more severely ill during their hospital stay had more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations, and are the main target population for intervention of long-term recovery.
FUNDING: National Natural Science Foundation of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Key Research and Development Program of China, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, and Peking Union Medical College Foundation.
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Manuel Taboada, Agustín Cariñena, Esther Moreno, Nuria Rodríguez, María Jesús Domínguez, Ana Casal, Vanessa Riveiro, María Diaz-Vieito, Luis Valdés, Julián Álvarez, Teresa Seoane-Pillado
Post-COVID-19 functional status six-months after hospitalization.
J Infect. 2020 Dec 26;. doi: 10.1016/j.jinf.2020.12.022. Epub 2020 Dec 26.
Abstract/Text
