Tag: Q fever

A possible role for mitochondrial-derived peptides humanin and MOTS-c in patients with Q fever fatigue syndrome and chronic fatigue syndrome

Abstract:

Background: Q fever fatigue syndrome (QFS) is a well-documented state of prolonged fatigue following around 20% of acute Q fever infections. It has been hypothesized that low grade inflammation plays a role in its aetiology. In this study, we aimed to identify transcriptome profiles that could aid to better understand the pathophysiology of QFS.

Methods: RNA of monocytes was collected from QFS patients (n = 10), chronic fatigue syndrome patients (CFS, n = 10), Q fever seropositive controls (n = 10), and healthy controls (n = 10) who were age- (± 5 years) and sex-matched. Transcriptome analysis was performed using RNA sequencing.

Results: Mitochondrial-derived peptide (MDP)-coding genes MT-RNR2 (humanin) and MT-RNR1 (MOTS-c) were differentially expressed when comparing QFS (− 4.8 log2-fold-change P = 2.19 × 10−9 and − 4.9 log2-fold-change P = 4.69 × 10−8), CFS (− 5.2 log2-fold-change, P = 3.49 × 10−11 − 4.4 log2-fold-change, P = 2.71 × 10−9), and Q fever seropositive control (− 3.7 log2-fold-change P = 1.78 × 10−6 and − 3.2 log2-fold-change P = 1.12 × 10−5) groups with healthy controls, resulting in a decreased median production of humanin in QFS patients (371 pg/mL; Interquartile range, IQR, 325–384), CFS patients (364 pg/mL; IQR 316–387), and asymptomatic Q fever seropositive controls (354 pg/mL; 292–393).

Conclusions: Expression of MDP-coding genes MT-RNR1 (MOTS-c) and MT-RNR2 (humanin) is decreased in CFS, QFS, and, to a lesser extent, in Q fever seropositive controls, resulting in a decreased production of humanin. These novel peptides might indeed be important in the pathophysiology of both QFS and CFS.

Source: Ruud P. H. Raijmakers, Anne F. M. Jansen, Stephan P. Keijmel, Rob ter Horst, Megan E. Roerink, Boris Novakovic, Leo A. B. Joosten, Jos W. M. van der Meer, Mihai G. Netea and Chantal P. Bleeker-Rovers. A possible role for mitochondrial-derived peptides humanin and MOTS-c in patients with Q fever fatigue syndrome and chronic fatigue syndrome. Journal of Translational Medicine 2019 17:157  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1906-3  (Full article)

Cytokine profiles in patients with Q fever fatigue syndrome

Abstract:

Background: Q fever fatigue syndrome (QFS) is a state of prolonged fatigue following around 20% of acute Q fever cases. It is thought that chronic inflammation plays a role in its aetiology. To test this hypothesis we measured circulating cytokines and the exvivo cytokine production in patients with QFS and compared to various control groups.

Materials/methods: Peripheral blood mononuclear cells (PBMCs), whole blood, and serum were collected from 20 QFS patients, 19 chronic fatigue syndrome (CFS) patients, 19 Q fever seropositive controls, and 25 age- and sex-matched healthy controls. Coxiella-specific ex-vivo production of tumor necrosis factor (TNF)α, interleukin (IL)-1β, IL-6, and interferon (IFN) was measured, together with a total of 92 circulating inflammatory proteins.

Results: PBMCs of QFS patients produced more IL-6 (P = 0.0001), TNFα (P = 0.0002), and IL-1β (P = 0.0005) than the various control groups when stimulated with Coxiella antigen. QFS patients had distinct differences in circulating inflammatory markers compared to the other groups, including higher concentrations of circulating IL-6 and IFNγ.

Conclusion: QFS patients showed signs of chronic inflammation compared to asymptomatic Q fever seropositive controls, CFS patients, and healthy controls, of which the monocyte-derived cytokines TNFα, IL-1β, and especially IL-6, are likely crucial components.

Source: Raijmakers, Ruud P.H. et al. Cytokine profiles in patients with Q fever fatigue syndrome. Journal of Infection , Volume 0 , Issue 0 , DOI: https://doi.org/10.1016/j.jinf.2019.01.006

Interferon-γ and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome

Abstract:

Approximately 20% of patients with acute Q fever develop Q fever fatigue syndrome (QFS), a debilitating fatigue syndrome. This study further investigates the role of C. burnetii-specific IFNγ, but also IL-2, CXCL9, CXCL10, and CXLC11 production in QFS patients. C. burnetii-specific IFNy, IL-2, CXCL9, CXCL10, and CXCL11 production were tested in ex vivo stimulated whole blood of QFS patients who recovered from their complaints (n = 8), QFS patients with persisting complaints (n = 27), and asymptomatic Q fever seropositive controls (n = 10).

With the exclusion of one outlier, stimulation with C. burnetii revealed significantly higher IFNy and CXCL10 production in QFS patients with persisting complaints (medians 288.0 and 176.0 pg/mL, respectively) than in QFS patients who recovered from their complaints (medians 93.0 and 85.5 pg/mL, respectively) (p = 0.041 and 0.045, respectively). No significant differences between groups were found for C. burnetii-specific IL-2, CXCL9, and CXCL11 production.

These findings point towards a difference in cell-mediated immunity in QFS patients with persisting complaints compared to those who recovered from their complaints. Such a difference may aid to eventually diagnose QFS more objectively and might serve as an indicator of its underlying etiology.

Source: Raijmakers RPH, Jansen AFM, Keijmel SP, Schoffelen T, Scholzen A, van der Meer JWM, Joosten LAB, Netea MG, van Deuren M, Bleeker-Rovers CP. Interferon-γ and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome. Eur J Clin Microbiol Infect Dis. 2018 Jul;37(7):1385-1391. doi: 10.1007/s10096-018-3265-z. Epub 2018 May 26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015096/ (Full article)

Chronic fatigue syndrome after Q fever

Abstract:

BACKGROUND: Q fever is a common and acute but rare chronic zoonosis caused by Coxiella burnetii. Its acute form manifests as atypical pneumonia, flu-like syndrome, or hepatitis. Some authors observed symptoms of chronic fatigue in a small number of patients after the acute phase of Q fever; in many cases serological assay confirmed the activity of Coxiella burnetii infection. The effect of antibiotic therapy on post-Q-fever fatigue syndrome has not been studied in south-east Europe thus far.

CASE REPORTS: Three patients are presented with post-Q-fever fatigue syndrome. All fulfilled the CDC criteria for chronic fatigue syndrome. IgA antibodies to phase I of the growth cycle of Coxiella burnetii were positive in two patients and negative in one. Two patients were treated with doxycycline for two weeks in the acute phase of illness and one with a combination of erythromycin and gentamycin. After 4-12 months they developed post-Q-fever fatigue syndrome and were treated with intracellular active antibiotics (fluoroquinolones and tetracycline) for 3-12 months. Efficacy of the treatment was observed in two patients, but in one patient the results were not encouraging.

CONCLUSIONS: These results suggest the possibility of the involvement of Coxiella burnetii infection in the evolution of chronic fatigue syndrome. This is the first report on post-Q-fever fatigue syndrome in Mediterranean countries. Evidence of IgA antibodies to phase I of the growth cycle of Coxiella burnetii is not a prerequisite for establishing a diagnosis of CFS. The recommendation of antibiotic treatment in post-Q-fever fatigue syndrome requires further investigation.

 

Source: Ledina D, Bradarić N, Milas I, Ivić I, Brncić N, Kuzmicić N. Chronic fatigue syndrome after Q fever. Med Sci Monit. 2007 Jul;13(7):CS88-92. https://www.ncbi.nlm.nih.gov/pubmed/17599032

 

Treatment of chronic fatigue syndrome with antibiotics: pilot study assessing the involvement of Coxiella burnetii infection

Abstract:

OBJECTIVE: To examine whether Coxiella burnetii (C. burnetii) is involved in chronic fatigue syndrome (CFS), we administered tetracycline antibiotics to subjects with CFS, and followed changes in clinical symptoms, PCR findings, and C. burnetii antibody titers.

PATIENTS AND METHODS: The subjects were 8 patients with CFS and 213 with nonspecific complaints such as chronic fatigue and low-grade fever for several months or longer but not meeting the diagnostic criteria for CFS. All were examined for C. burnetii infection by nested PCR and the indirect immunofluorescence test (IF).

RESULTS: Four CFS patients (the CFS group) and 54 controls [the post-Q fever fatigue syndrome (QFS) group] positive for C. burnetii were treated mainly with minocycline or doxycycline (100 mg/day) for 3 months. After treatment, all 58 patients tested negative for C. burnetii infection. In the CFS group, no significant difference was noted between the mean pre- and post-treatment temperatures or headache scores. Similarly, there was no significant improvement in performance status (PS) scores. In the QFS group, however, mean temperatures and headache scores were significantly decreased after treatment (p<0.001). PS scores were also improved.

CONCLUSION: These results suggest the possibility of direct involvement of C. burnetii in the pathological state of CFS to be low, despite the C. burnetii infection rate being high in CFS patients. This is a pilot study and further larger investigations are necessary to confirm our preliminary results.

 

Source: Iwakami E1, Arashima Y, Kato K, Komiya T, Matsukawa Y, Ikeda T, Arakawa Y, Oshida S. Treatment of chronic fatigue syndrome with antibiotics: pilot study assessing the involvement of Coxiella burnetii infection. Intern Med. 2005 Dec;44(12):1258-63. https://www.ncbi.nlm.nih.gov/pubmed/16415546

 

Variation in immune response genes and chronic Q fever. Concepts: preliminary test with post-Q fever fatigue syndrome

Abstract:

Acute primary Q fever is followed by various chronic sequelae. These include subacute Q fever endocarditis, granulomatous reactions in various organs or a prolonged debilitating post-infection fatigue syndrome (QFS). The causative organism, Coxiella burnetii, persists after an initial infection. The differing chronic outcomes may reflect variations within cytokine and accessory immune control genes which affect regulation of the level of persistence. As a preliminary test of the concept we have genotyped QFS patients and controls for gene variants spanning 15 genes and also examined HLA-B and DR frequencies. QFS patients exhibited a significantly increased frequency of HLA-DR-11 compared with controls and also significant differences in allelic variant frequencies within the NRAMP, and IFN gamma genes. These results indicate a possible genetic role in the expression of overt chronic Q fever. Further studies will be undertaken to increase sample sizes, to survey other forms of chronic Q fever and to examine Q fever patients who have recovered without sequelae.

 

Source: Helbig KJ, Heatley SL, Harris RJ, Mullighan CG, Bardy PG, Marmion BP. Variation in immune response genes and chronic Q fever. Concepts: preliminary test with post-Q fever fatigue syndrome. Genes Immun. 2003 Jan;4(1):82-5. http://www.ncbi.nlm.nih.gov/pubmed/12595908

 

Long-term follow-up of patients from the 1989 Q fever outbreak: no evidence of excess cardiac disease in those with fatigue

Abstract:

BACKGROUND: In 1989, an outbreak of Q fever (C. burnetii infection) with 147 confirmed cases occurred in Solihull, West Midlands. Three patients developed cardiomyopathy in the subsequent 10 years. The cohort has been followed up with respect to the development of fatigue and, in this instance, cardiac effects after the original infection.

AIM: To determine whether persisting fatigue after Q fever represented sub-clinical cardiomyopathy.

DESIGN: Prospective follow-up study.

METHODS: All traceable subjects from the original outbreak, and community age-, sex- and smoking-matched controls, were studied. Questionnaires for idiopathic fatigue, 12-lead ECG, echocardiography, spirometry and shuttle walk distance were undertaken, and a subset with CDC-defined chronic fatigue syndrome had gated cardiac scans.

RESULTS: Of the original cohort, 19 had died, three had emigrated and 10 were untraceable. Of the remaining 115, 108 responded to a mailed questionnaire and 87 were investigated further, of whom 85 provided complete data. Two developed aortic valve vegetations, one of whom died. Chronic fatigue syndrome was found in 20% of cases and 5.3% of controls (including those with co-morbidities), falling to 8.2% and 0 when excluding those with co-morbidities. There were no significant differences in ECG and echocardiographic investigations or shuttle-walk distance between those with fatigue and those without. Six of the seven patients with CFS had gated cardiac scans: all were within normal limits.

CONCLUSIONS: These findings do not support the existence of a sub-clinical cardiomyopathy in the patients in this cohort who suffer from fatigue after acute Q fever, although endocarditis can occur after acute infection.

Comment in: Q fever: still a mysterious disease. [QJM. 2002]

 

Source: Ayres JG, Wildman M, Groves J, Ment J, Smith EG, Beattie JM. Long-term follow-up of patients from the 1989 Q fever outbreak: no evidence of excess cardiac disease in those with fatigue. QJM. 2002 Aug;95(8):539-46. http://qjmed.oxfordjournals.org/content/95/8/539.long (Full article)

 

Chronic fatigue following infection by Coxiella burnetii (Q fever): ten-year follow-up of the 1989 UK outbreak cohort

Abstract:

BACKGROUND: Some patients exposed to Q fever (Coxiella burnetii infection) may develop chronic fatigue.

AIM: To determine whether subjects involved in the West Midlands Q fever outbreak of 1989 had increased fatigue, compared to non-exposed controls, 10 years after exposure.

DESIGN: Matched cohort study comparing cases to age-, sex- and smoking-history-matched controls not exposed to Q fever.

METHODS: A postal questionnaire was sent to subjects at home, followed by further assessment in hospital, including a physical examination and blood tests.

RESULTS: Of 108 Q-exposed subjects, 70 (64.8%) had fatigue, 37 idiopathic chronic fatigue (ICF) (34.3%), vs. 29/80 (36.3%) and 12 (15.0%), respectively, in controls. In 77 matched pairs, fatigue was commoner in Q-exposed subjects than in controls: 50 (64.9%) vs. 27 (35.1%), p<0.0001. ICF was found in 25 (32.5%) of Q-exposed patients and 11(14.3%) of controls (p=0.01). There were 36 (46.8%) GHQ cases in Q-exposed subjects, vs. 18 (23.4%) controls (p=0.004). A matched analysis of those more intensively studied showed fatigue in 48 (66.7%) Q-exposed patients and 25 (34.7%) controls, (p<0.0001), ICF in 25 (34.7%) Q-exposed and 10 (13.9%) controls (p=0.004), and chronic fatigue syndrome (CFS) in 14 (19.4%) Q-exposed patients and three (4.2%) controls (p=0.003). Thirty-four (47.2%) Q-exposed patients were GHQ cases compared to 17 (23.6%) controls (p=0.004).

DISCUSSION: Subjects who were exposed to Coxiella in 1989 had more fatigue than did controls, and some fulfilled the criteria for CFS. Whether this is due to ongoing antigen persistence or to the psychological effects of prolonged medical follow-up is uncertain.

Comment in: Q fever: still a mysterious disease. [QJM. 2002]

 

Source: Wildman MJ, Smith EG, Groves J, Beattie JM, Caul EO, Ayres JG. Chronic fatigue following infection by Coxiella burnetii (Q fever): ten-year follow-up of the 1989 UK outbreak cohort. QJM. 2002 Aug;95(8):527-38. http://qjmed.oxfordjournals.org/content/95/8/527.long (Full article)

 

Cytokine dysregulation in the post-Q-fever fatigue syndrome

Abstract:

The post-Q-fever fatigue syndrome (QFS) (inappropriate fatigue, myalgia and arthralgia, night sweats, changes in mood and sleep patterns) follows about 20% of laboratory-proven, acute primary Q-fever cases. Cytokine dysregulation resulting from chronic immune stimulation and modulation by persistence of Coxiella burnetii cells or their antigens is hypothesized.

We studied cytokine release patterns of peripheral blood mononuclear cells (PBMC) stimulated with various ligands in short-term culture, from 18 patients with active QFS, and 27 controls: six with resolving QFS, five who had had acute primary Q-fever without subsequent QFS, eight healthy Q-fever vaccinees and eight healthy subjects without Q-fever antibody. Conditioned media (CM) from PBMC stimulated in short-term culture with Q-fever antigens, PHA or measles antigen (as an unrelated antigen) were assayed for IL-2, IL-4, IL-5, IL-6, IL-10 and IFN gamma by AgEIA, and for IL-1 and TNF alpha/beta by bioassay.

Aberrant cytokine release patterns were observed with PBMC from QFS patients when stimulated with Q-fever antigens: an accentuated release of IL-6 which was significantly [p = 0.01, non-parametric one-way analysis of variance (ANOVA)] in excess of medians for all four control groups. With IL-2, the number of responders in the active QFS group was decreased relative to control groups (Fisher’s exact test, p = 0.01) whereas the number of IFN gamma responders was increased (Fisher’s exact test, p = 0.0008). Significant correlations were observed between concentrations of IL-6 in CM, total symptom scores, and scores for other key symptoms.

Comment in: Fatigue syndromes. [QJM. 1999]

 

Source: Penttila IA, Harris RJ, Storm P, Haynes D, Worswick DA, Marmion BP. Cytokine dysregulation in the post-Q-fever fatigue syndrome. QJM. 1998 Aug;91(8):549-60. http://qjmed.oxfordjournals.org/content/91/8/549.long (Full article)

 

Post-infection fatigue syndrome following Q fever

Abstract:

In 1989, 147 individuals in the West Midlands, UK, were infected with Q fever. Five years later, following anecdotal reports of fatigue, we used a questionnaire-based case-control study to determine the prevalence of chronic fatigue syndrome symptoms in this group.

Replies from 71 patients were compared with those from 142 age- and sex-matched controls. Increased sweating (52.9% vs. 31.6%, p = 0.006), breathlessness (50.7% vs. 30.6%, p = 0.006), blurred vision (34.3% vs. 17.8%, p = 0.016) and undue tiredness (68.7% vs. 51.5%, p = 0.03) were found in controls compared to cases. These findings were similar to those in Australian abbatoir workers occupationally exposed to Q fever.

CDC criteria for chronic fatigue syndrome were fulfilled by 42.3% of cases and 26% of controls. Using visual analogue scores, symptoms were more severe in cases than in controls. Our findings support the existence of a chronic fatigue state following acute Q fever, in a group of patients exposed just once to the organism, and in circumstances free of such confounding factors as lawsuits over compensation.

 

Source: Ayres JG, Flint N, Smith EG, Tunnicliffe WS, Fletcher TJ, Hammond K, Ward D, Marmion BP. Post-infection fatigue syndrome following Q fever. QJM. 1998 Feb;91(2):105-23. http://qjmed.oxfordjournals.org/content/91/2/105.long