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Table 1 Overview of studies measuring IL-1 in patients reporting fatigue

From: Interleukin-1 as a mediator of fatigue in disease: a narrative review

Reference Disease activity Number of patients Fatigue questionnaire IL-1 measurement Main outcome
Rheumatoid arthritis
 Lampa et al., 2014 No neurological disease or generalized pain nor of swollen joints 4.9 ± 3.8 Patients (n = 14), controls (n = 12) VAS-fatigue CSF IL-1 and IL-1Ra Higher IL-1β and lower IL-Ra in RA vs controls (p < 0.001, p < 0.05), positive correlation between IL-1β and fatigue (R = 0.55, p < 0.05)
Sjögrens syndrome
 Harboe et al., 2009 No acute illness in the week prior to or after sampling, no CRP/ESR elevation Patients (n = 54), controls (n = 53) FSS, VAS-fatigue CSF IL-1β, IL-1Ra, and IL-1sRII Higher IL-1Ra in patients (p = 0.026), correlation IL-1Ra and VAS-fatigue (R 2 = 0.11, p = 0.015).
Sarcoidosis
 Korenromp et al., 2011 No disease activity Fatigued patients (n = 34), non-fatigued patients (n = 38) CIS-fatigue (severe fatigue when ≥35) Plasma IL-1α, IL-1β, and IL-1Ra No significant differences
     Whole blood production of IL-1α and IL-1β after stimulation with LPS (1 ng/ml)  
 Baydur et al., 2010 Pulmonary sarcoidosis Patients (n = 22), controls (n = 22) MFI-20 Plasma IL-1β before, directly after and 4–6 h after exercise Higher fatigue scores in sarcoidosis patients (p < 0.0001). IL-1β not different between patients and controls or among the three collection times. Correlation between pre-exercise IL-1β and MFI-20 in patients receiving immunomodulatory medication (R 2 0.63, p = 0.03).
Cancer
Mixed (cancer survivors plus advanced cancer)
 De Raaf et al., 2012 Advanced cancer or 1–5 years post cancer treatment Advanced cancer (n = 45), cancer survivors (n = 47) MFI Plasma IL-1Ra Advanced cancer patients had higher IL-1Ra concentrations (p < 0.01). In these patients, physical fatigue was correlated with IL-1Ra (r = 0.32, p = 0.03). In cancer survivors, IL-1Ra was related to both physical (r = 0.24, p = 0.10) and mental fatigue (r = 0.35, p = 0.02).
Prostate cancer
 Greenberg et al.,1993 Men undergoing localized radiotherapy Patients (n = 15) VAS-fatigue/daily during 8 weeks Serum IL-1β, at baseline and weekly thereafter A rise in fatigue was seen between weeks 1 and 4, fatigue stabilized during week 5 and increased again in weeks 6 and 7. Rise in fatigue during the first 4 weeks was accompanied by increased IL-1β concentrations (p-value not reported).
 Bower et al., 2009 Patients undergoing external beam radiation therapy Prostate cancer (n = 20), breast cancer (n = 28) FSI/fatigue during the past week/baseline, after 5/10/20 days of treatment, final week of treatment, and 2 weeks and 2 months after treatment Serum IL-1β, IL-1Ra in a subset of patients, at same time-points as the questionnaires Fatigue increased in both groups during treatment. Significant quadratic trend for IL-1β during treatment (p = 0.034). Treatment dose was not associated with IL-1β and IL-1Ra concentrations. There was no correlation between IL-1β and fatigue severity. IL-1Ra was associated with fatigue (β = 0.63, p = 0.016).
 Dirksen et al., 2014 Non-metastatic cancer prior to radiation therapy Patients (n = 30) POMS fatigue (inertia subscale)/pre-treatment en post-treatment Serum IL-1β, pre-treatment and post-treatment (<2 weeks after radiotherapy, <10 weeks after brachytherapy) Fatigue was increased post-treatment (p = 0.027). No differences in IL-1β concentrations, no correlation with fatigue severity
 Jim et al., 2012 Non-metastatic or asymptomatic metastatic prostate cancer Patients (n = 53) FSI (fatigue over the past week)/at baseline and after 6 months SNP in IL1B gene (rs16944) IL1B had no significant effect on fatigue-related outcomes
Breast cancer
 Geinitz et al., 2000 Women undergoing postoperative radiotherapy (no chemotherapy), without metastatic disease Patients (n = 41) FAQ, and VAS-fatigue/during previous week/at baseline, end of weeks 1–5, and 2 months after treatment Serum IL-1β, same time points as questionnaires VAS-fatigue increased until week 4 (p < 0.001). During weeks 4 and 5 FAQ physical (p = 0.035 and 0.015) and cognitive (p = 0.008 and 0.007) subscales were significantly elevated. IL-1β did not increase during treatment.
 Von Ah et al., 2008 Stage 0–IIIa breast cancer before adjuvant therapy Patients (n = 44) Piper-fatigue scale/at baseline and at 3 months (during adjuvant therapy) and 6 months after baseline (initial recovery) Whole blood production of IL-1β after stimulation with PHA (10 μg/ml) IL-1β predicted fatigue before adjuvant therapy (β = 0.30, p < 0.05).
 Liu et al., 2012 Stage I–III breast cancer prior to ≥4 3-week cycles of chemotherapy Patients (n = 53) MFSI-SF/fatigue during past week/at baseline and during cycles 1 and 4 of chemotherapy (last 2 weeks) Plasma IL-1Ra, at the same time points as questionnaires Fatigue significantly increased over time (p < 0.05). IL-1Ra dropped at cycle 1 week 3 (p < 0.0001). There was no association between IL-1Ra and fatigue.
 Schmidt et al., 2015 Stage 0–III breast cancer prior to adjuvant radiation therapy Patients (n = 92) FAQ/at baseline, after completion of radiotherapy (week 7), and the end of the intervention (week 13, resistant exercise/relaxation) Serum IL-1Ra, at the same time points as questionnaires Moderate correlation between IL-6/IL-1Ra at the end of radiotherapy with physical fatigue at the same time (r = 0.25, p = 0.022) and at 6 weeks after chemotherapy (r = 0.23, p = 0.046).
 Bower et al., 2002 Stage 0–II breast cancer 1–5 years after diagnosis, after completion of treatment Fatigued (n = 20), non-fatigued (n = 20) Energy/fatigue subscale RAND-36 (score 0–50 = high fatigue, score 70–100 = low fatigue)/fatigue during past 4 weeks FSI/fatigue during past week Serum IL-1β and IL-1Ra Fatigued women had significantly higher IL-1Ra concentrations (p = 0.006).
 Bower et al., 2011 Stage 0–IIIA breast cancer, after completion of primary cancer therapy (within past 3 months) i.e., surgery, radiation, and/or chemotherapy Patients (n = 103) FSI (cut-off 3)/fatigue during the past week Plasma IL-1Ra 64% scored above 3 on the FSI; these patients did not have a higher IL-1Ra concentration. There was no significant association between IL-1Ra and fatigue or chemotherapy exposure.
 Bower et al., 2007 Stage 0–II breast cancer survivors (6.5–10 years after diagnosis) Fatigued (n = 10), non-fatigued (n = 15) Vitality scale SF-36 (<50 = significant fatigue, >70 = absence of significant fatigue) Whole blood production of IL-1β after stimulation with LPS (100 pg/ml) or cortisol (0, 10−8, 107, 10−6M), at baseline, directly after TSST, and after 30 min recovery No differences at baseline. IL-1β increased significantly in fatigued patients after completion of the TSST (p = 0.02).
 Collado-Hidalgo et al., 2006 Stage 0–III breast cancer survivors, 1–5 years post-diagnosis Fatigued (n = 32), non-fatigued (n = 18) Vitality scale SF-36 (<50 = significant fatigue, >70 = absence of significant fatigue) Plasma IL-1Ra IL-1Ra was significantly higher in fatigued breast-cancer survivors (p = 0.05).
 Orre et al., 2011 Stage II–III breast cancer patients, 2.7–7.2 years after postoperative locoregional radiotherapy Patients (n = 299) Fatigue questionnaire Serum IL-1Ra There was no significant association between IL-1Ra and fatigue.
 Collado-Hidalgo et al., 2009 Stage 0–III breast cancer survivors, 1–5 years post-diagnosis Fatigued (n = 33), non-fatigued (n = 14) Vitality scale SF-36 (≤55 = significant fatigue, >70 = absence of significant fatigue), MFSI IL-1B-511 (CT) polymorphism Fatigued survivors had a substantial overrepresentation of CC alleles, and underrepresentation of TT alleles. The prevalence of at least one cytosine was more frequent among fatigued patients (p = 0.007) and associated with fatigue in multiple regression (p = 0.021). Which was no longer significant after controlling for depressive symptoms (p = 0.052).
 Reinertsen et al., 2011 Stage II–III breast cancer survivors Fatigued (n = 101), non-fatigued (n = 201) Fatigue questionnaire (cut-off 4, clinical significant fatigue), chronic fatigue was defined as fatigue being present for at least 6 months IL-1B rs16944 (A/G) SNP, and IL-1β mRNA expression There was no association between chronic fatigue and the IL-1B SNP or IL-1β mRNA expression.
Testicular cancer
 Orre et al., 2009 Patients 5–20 years after unilateral orchiectomy Fatigued (n = 92), non-fatigued (n = 191) Fatigue questionnaire (cut-off 4, clinical significant fatigue), chronic fatigue was defined as fatigue being present for at least 6 months Plasma IL-1Ra Fatigued patients had significant higher IL-1Ra (p = 0.002). In multiple regression analysis, IL-1Ra corrected for age had an OR of 1.93 (95%CI 1.21–3.08). Although age an IL-1Ra explained only 4% of the variance. IL-1Ra was not included in the final model.
Uterine cancer
 Ahlberg et al., 2004 Patients receiving external radiation therapy after hysterectomy Patients (n = 15) MFI-20/at baseline, after 30Gy (+3 weeks) and after 46Gy (+5–6 weeks) Plasma IL-1 (α or β unknown), same time-points as questionnaires Fatigue increased during treatment, IL-1 remained below the detection limit during the entire study period (4 pg/ml).
AML/MDS
 Meyers et al., 2005 Newly diagnosed AML/MDS before undergoing chemotherapy. Patients (n = 54) Brief fatigue inventory (cut-off score ≥4, moderate-severe fatigue)/fatigue in the past 24 h/baseline and after 1 month of treatment Plasma IL-1 (α or β unknown) and IL-1Ra, at baseline. There was a positive correlation of IL-1Ra and fatigue (r = 0.52, p value not reported).
Post-stroke fatigue
 Ormstad et al., 2011 Acute stroke patients Patients (n = 45) FSS (dichotomized as a score ≥4 or <4)/at 6, 12, and 18 months after stroke Serum IL-1β and IL-1Ra, <24h (n = 35), 24–48 h (n = 7), and 48–72 h (n = 3) after stroke onset Significant correlation between IL-1β and fatigue at 6 months (r = 0.37, p = 0.015). Negative correlation between IL-1Ra and fatigue at 12 months (r = −0.38, p = 0.013). Fatigued patients had significant lower IL-1Ra concentrations.
 Becker et al., 2015 Acute stroke patients Patients (n = 39) FAS/30/90/180/365 days after stroke IL1RN SNP rs4251961 Carriers of a C allele reported more fatigue (p = 0.03). At 30 and 90 days, patients with at least one C allele had higher scores on fatigue (p < 0.05).
CFS
 Hornig et al., 2015 CFS Patients (illness duration ≤3 years n = 52, illness duration >3 years n = 246), controls (n = 348) MFI Plasma IL-1α, IL-1β and IL-1Ra There were no differences when comparing all patients combined to controls. However, patients with a short illness duration had significantly higher IL-1α (p < 0.05) and IL-1Ra (p < 0.05) compared to controls. In patients with a long illness duration, IL-1β was significantly lower compared to controls (p < 0.05). IL-1α, IL-1β and IL-1Ra were higher in short illness patients compared to long illness patients (p < 0.01).
 Russell et al., 2016 CFS (female) Patients; 1. ≤18/illness duration ≤2 years (n = 18), 2. age 18–50/average illness duration 7 years (n = 22), 3. age ≥50 and average illness duration 11 years (n = 28), controls (n = 81) Chalder fatigue in adolescents, and MFI in other patients Plasma IL-1α and IL-1β Looking at individual expression, there were no differences between patients and controls. IL-1α appeared in a linear classification model in the adolescent group, but not in the other 2 groups.
 Hardcastle et al., 2015 Moderate (mobile) or severe (housebound) CFS Moderate CFS (n = 22), severe CFS (n = 19), controls (n = 22) FSS Serum IL-1β and IL-1Ra Significant IL-1β increase in moderate compared with severe CFS patients (p = 0.002). For other subgroups and IL-1Ra there were no differences.
 Landi et al., 2016 CFS Patients (n = 100), controls (n = 79) MFI Plasma IL-1α and IL-1β No significant differences.
 Chao et al., 1991 CFS Patients (n = 9), controls (n = 7) VAS-fatigue Serum IL-1β No differences in serum IL-1β. IL-1β production after LPS stimulation was significantly higher in CFS patients (p < 0.05)
     PBMC production of IL-1β after stimulation with LPS (1 ng/ml) or PHA (4 μg/ml)  
 Swanink et al., 1996 CFS Patients (n = 76), controls (n = 69) CIS Plasma IL-1α, IL-1β, and IL-1Ra No differences in circulating cytokine concentrations. Significant lower IL-1β production after LPS stimulation (p < 0.05), no correlation between production and fatigue severity.
     Whole blood production of IL-1α, IL-1β, and IL-1Ra after stimulation with LPS  
 Mawle et al., 1997 CFS Patients (n = 26), controls (n = 50) PBL production of IL-1α and IL-1β after stimulation with PHA IL-1α production was lower in severely ill patients (n = 13) and those with a gradual disease onset (n = 17) compared to controls (p = 0.038, p = 0.011). IL-1β was also lower in patients with a gradual disease onset (p = 0.039).
 Cannon et al., 1997 Sudden onset CFS Patients (n = 16), controls (n = 15) PBMC production of IL-1β, IL-1Ra, and IL-1sRII after stimulation with LPS (1 ng/ml), indomethacin, or a combination, before and daily after a 15 min exercise on day 2 At baseline, controls had a significant increase in IL-1β production during the luteal phase (unstimulated, p = 0.021). This increase was absent in CFS patients. In the follicular phase, control group had an increase IL-1β production 48 h after exercise. In CFS patients, there was no alteration over time. In the follicular phase, IL-1Ra secretion was higher in CFS patients (unstimulated, p = 0.023). IL-1sRII was higher in patients (unstimulated, p = 0.0002).
 Tomoda et al., 2005 CFS Patients (n = 15), controls (n = 23) IL-1β production of PBMCs after stimulation with PHA (5 μg/ml) or LPS (50 ng/ml) No significant differences.
 Lloyd et al., 1991 CFS Patients (n = 25), controls (n = 28) Serum and CSF IL-1β No significant differences.
 Peterson et al., 2015 CFS Patients (n = 18), controls (n = 5) CSF IL-1β and IL-1Ra No significant differences.
 Natelson et al., 2005 CFS Patients (n = 44), controls (n = 13) MFI CSF IL-1α and IL-1β No significant differences.
 Hornig et al., 2016 CFS Patients (n = 32), MS controls (n = 40), and controls (n = 19) CSF IL-1α, IL-1β and IL-1Ra CFS patients had significant lower IL-1β and IL-1Ra concentrations compared to normal controls (p = 0.003 and p = 0.014). And compared to MS patients IL-1α (p = 0.0007), IL-1β (p = 0.0018) and IL-1Ra (p = 0.0003) were decreased in CFS.
(Post-)infectious fatigue
 Vollmer-Conna et al., 2004 Patients with acute Q-fever, EBV, or RRV Q-fever (n = 18), EBV (n = 24), RRV (n = 24) Physical symptom checklist/fatigue in the past 2 weeks Serum IL-1β Fatigue was reported in 100% of Q-fever patients, >75% of EBV patients, and >50% of RRV patients. In Q-fever, IL-1β correlated significantly with fatigue (r = 0.47, p = 0.04), which was also found in the EBV/RRV combination group (r = 0.39, p = 0.01). All significant results were obtained from the unstimulated samples.
     PBMC production of IL-1β after stimulation with LPS (10 ng/ml)  
 Vollmer-Conna et al., 2007 Patients with post-infectious fatigue and post-infectious patients without fatigue EBV (n = 11), RRV (n = 6), Q-fever (n = 5), and controls after EBV (n = 17), RRV (n = 14) or Q-fever (n = 11) Somatic and psychological health report (fatigue was defined as a score ≥3 on the SOMA subscale)/at 1, 2, 3, 6, and 12 months after onset of the infection Serum IL-1β No significant differences.
     PBMC production of IL-1β after stimulation with LPS (10 ng/ml), mouse anti-human or anti-CD3  
  1. An overview of all studies that investigated the relationship between IL-1 and fatigue severity
  2. Abbreviations: AML acute myeloid leukemia, CFS chronic fatigue syndrome, CSF cerebrospinal fluid, CIS checklist individual strength, CRP C-reactive protein, EBV Epstein-Barr virus, ESR erythrocyte sedimentation rate, FAS fatigue assessment scale, FAQ functional activity questionnaire, FSI fatigue symptom inventory, FSS fatigue severity scale, LPS lipopolysaccharide, MDS myelodysplastic syndrome, MFI multidimensional fatigue inventory, MFSI multidimensional fatigue symptom inventory, MS multiple sclerosis, PBL peripheral blood leukocytes, PBMC peripheral blood mononuclear cell, PHA phytohaemagglutinin, POMS profile of mood states, RRV Ross river virus, SF short form, TSST Trier social stress test, VAS visual analog scale