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Azithromycin in Chronic Fatigue Syndrome (CFS), an analysis of clinical data
Journal of Translational Medicine volume 4, Article number: 34 (2006)
CFS is a clinical state with defined symptoms, but undefined cause. The patients may show a chronic state of immune activation and treatment with an antibiotic in this subgroup has been suggested.
In a retrospective study, the response of CFS patients to azithromycin, an antibiotic and immunomodulating drug, has been scored from the patients records and compared with clinical and laboratory data. Azithromycin was not the first choice therapy, but offered when the effect of counseling and L-carnitine was considered insufficient by the patient and the clinician.
Of the 99 patients investigated, 58 reported a decrease in the symptoms by the use of azithromycin. These responding patients had lower levels of plasma acetylcarnitine.
The efficacy of azithromycin in the responsive patients could be explained by the modulating effect on a chronic primed state of the immune cells of the brain, or the activated peripheral immune system. Their lower acetylcarnitine levels may reflect a decreased antioxidant defense and/or an increased consumption of acetylcarnitine caused by oxidative stress.
In 1994 Fukuda et al.  defined CFS as a chronic persistent fatigue that is present for over 6 months, is not caused by activity nor alleviated by rest and accompanied with at least 4 other symptoms: cognitive impairment, pain in joints, muscles or head, unrefreshing sleep, soar throat, tender lymph nodes and postexertional malaise with slow recovery. Nevertheless, CFS remained subject to debate and even the mere existence of the syndrome was still questioned by some. The presentation of the results of quantitative morphology of the brain in CFS patients by Okada et al , later confirmed by De Lange et al  may change this opinion. The loss of grey matter in the brain, especially in Brodmann's area 9, was related to physical impairment, but not to the duration of the symptoms. Although other explanations were considered as well, this may indicate the occurrence of a major trauma to the brain at the start of the disease. This could also explain the low recovery rate in adults, because repair in adult brain is limited .
The severity of the sickness, both the symptoms and the lowered adaptation to physical stress, may fluctuate whenever infections and stress come and go. The Th1 to Th2 cytokine shift in CFS patients will make them more vulnerable to infections  and it has been suggested that they have more often chronic infections [6–8]. The predisposition for acquiring CFS may be genetically determined [9, 10], the occurrence is influenced by the severity of the immune response . The result is a chronic hyper-oxidative state of sickness [12, 13], in the brain itself  that cannot be stopped . Preliminary evidence of a relation between post-infectious fatigue and mitochondrial dysfunction indicates a complex response involving acetylcarnitine .
The clinical presentation of the symptoms and chances for recovery will depend on the balance between the irreversible loss of grey cells and activation of the immune system. According to De Meirleir et al, the presence of RNase-L and elastase may offer an indication for this balance [17–19]. Several treatment protocols to counteract the immune activation in CFS were presented [18, 20, 21], but the results were never validated in a double blind study. Such proof is required as a rationale for treatment and provides a basis to understand the pathophysiology of the disease. Comparing the outcome of clinical treatment protocols might add to our knowledge of CFS and its treatment until double blind studies are available .
Azithromycin is an antibiotic with immunomodulatory effects [23–25]. This antibiotic has been successfully used during periods of six months of more in other chronic diseases [26–28]. The side-effects are known for long term use and mainly limited to gastro-intestinal cramps. The chances for resistance limit its use to individual patients under close supervision . The drug is relatively inexpensive and extensive laboratory tests for side effects are not necessary. The result of a study in 10 CFS patients during 1 to 2 months was positive . We studied the medical records of CFS patients for clinical and laboratory data related to the outcome of the treatment with azithromycin.
In the CFS and Pain Research Center Amsterdam, patients are diagnosed with CFS according to the Fukuda criteria . Treatment protocols are discussed with the patient. One of the treatment protocols that were offered in our Center from April 2000 till August 2005 was azithromycin 500 mg on 3 consecutive days of the week during 6 weeks . Azithromycin was not a first choice therapy, but offered when the effect of counseling  and of L-carnitine during more than 3 months  was considered insufficient by the patient and the clinician. The period between the L-carnitine medication and the start of azithromycin was always longer than 2 weeks. The selection was not based on symptoms or laboratory indications of immune activity. This treatment was studied in a retrograde evaluation of the clinical records from April 2000 to August 2005. The change in the clinical condition as experienced by the patient (patient rated clinical global impression of change was scored as negative, neutral or positive after a standard interview ). The change had to be out of range of the previous fluctuations of the symptoms for scoring as improvement or deterioration. All patients signed an informed consent permitting the use of the data from the clinical records for evaluation and publication.
At the first visit all patients were evaluated according to the protocol of the 1994 consensus meeting . The severity of CFS was determined with the Stanford Health Assessment Questionnaire (SHAQ) , the Multidimensional Fatigue Inventory (MFI-20)  and the VAS-scale of the McGill Pain Questionnaire . The presence and severity of somatisation, distress, depression and anxiety was scored with the 4 Dimensional Symptom Questionnaire (4DSQ) . Questionnaires for disease specific symptoms were not available at the treatment period .
Free carnitine and carnitine esters in plasma were analyzed using tandem mass spectrometry as described by Vreken et al. .
Statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS 14.0 for Windows, Chicago, Ill).
Of the 99 patients who were treated with azithromycin, 58 (59%) reported an improvement of symptoms. No patients were worse at the end of the treatment. Side effects were minor bowel problems that resolved by dividing the daily dosage of azithromycin.
The majority of patients was female, 88% and 83% in the non-responder and responder group, respectively. The patients who reacted favorably, the responders, were younger, 34.7 ± 11.5 years (mean ± SD) versus 40.4 ± 12.6 (Student's t-test P = 0.023, 95% CI 0.8 and 10.5), but did not differ from the non-responders in fatigue score (MFI-20), somatisation, distress, depression and anxiety (4DSQ), pain score (VAS scale) or physical capacity (SHAQ) (Table 1). Neither the history, nor the physical examination was indicative for the response and the standard laboratory tests did not differ between the groups.
Plasma acetylcarnitine was lower in responders (4.78 ± 1.66 μM) compared to non-responders (5.87 ± 2.55) (P = 0.023, 95% CI 2.3 and 0.1). Plasma acetylcarnitine was 4.70 ± 1.70 μM in responding female patients (n = 48) and 4.61 ± 1.61 μM in responding men (n = 10) (P = 0.884, 95% CI -1.2 and 0.6). These levels were in non-responding female patients (n = 36) 6.04 ± 2.69 μM and in non-responding males (n = 5) 4.88 ± 1.17 μM (P = 0.412, 95% CI -1.7 and 1.4). Because of the absence of statistical difference between the responding females and males and also between the non-responding males and females, we took their values together and calculated that improvement was present in 77% of the patients with plasma acetylcarnitine concentration less than 4.1 μM, in 58% with acetylcarnitine between 4.1 and 6.5 μM and in 31% with acetylcarnitine higher than 6.5 μM. Free and the higher acylcarnitines were not different in responding females and males and non-responding females and males, and were also taken together (Table 2).
Fifty-nine percent of the patients reported improved symptoms of CFS after long-term use of azithromycin. This confirms the results reported by De Becker et al. . It is unlikely that this therapy is due to placebo response, because such a response is low in CFS (19.6%) . Medical history, physical examination, standard laboratory tests (data not shown) and questionnaires for the severity of symptoms (Table 1.) did not differentiate responders from non-responders. The reported change of symptoms differed greatly between patients and validated test for the severity of CFS-related symptoms was not available at that time. Therefore we decide to present an overall impression, based on a standard interview.
The more subtle sign of metabolic (oxidative) stress was reflected by the differences in plasma acetylcarnitine levels.
Significant differences in plasma acetylcarnitine [41, 42] were reported in CFS, while others found no difference [43, 44]. There are several explanations for this discrepancy. One explanation could be that the selection of CFS patients differed. The patients of Kuratsune et al. [41, 42] were selected according to the CDC criteria, but Jones et al  used the Oxford and CDC criteria.
The responders did not fully recover from CFS by azithromycin. They improved only to an estimated maximum of 80% of the pre-morbid capacity. There are two explanations for the improvement by azithromycin: A reduction of bacterial load  or the immune modulating effect of macrolides [23, 45]. If CFS is caused by a primed state of glia-cells in the brain  in a subgroup of patients, these cells would produce interleukin-1β at an increased rate as response to minor stimulation by stress or infection. The result is a chronic and fluctuating state of sickness that is not fully explained by the presence of an active and detectable disease state. Then it is likely that the immunomodulating drug azithromycin could improve the severity of CFS symptoms.
Lower plasma acetylcarnitine was observed in CFS patients who responded to azithromycin. The lower plasma acetylcarnitine level may indicate a decreased ability to counteract the action of the increased oxidative stress and/or an increased consumption of acetylcarnitine by the increased oxidative stress.
The response rate of 59% in this retrospective open study is not necessarily indicative for the effect rate in prospective blinded studies.
Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A, Schluederberg A, Jones JF, Lloyd AR, Wessely S, Gantz NM, Holmes GP, Buchwald D, Abbey S, Rest J, Levy JA, Jolson H, Peterson DL, Vercoulen JHMM: The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine. 1994, 121 (12): 953-959.
Okada T, Tanaka M, Kuratsune H, Watanabe Y, Sadato N: Mechanisms underlying fatigue: A voxel-based morphometric study of chronic fatigue syndrome. BMC Neurology. 2004, 4 (-): 6p-
De Lange FP, Kalkman JS, Bleijenberg G, Hagoort P, Van Der Meer JWM, Toni I: Gray matter volume reduction in the chronic fatigue syndrome. NeuroImage. 2005, 26 (3): 777-781. 10.1016/j.neuroimage.2005.02.037.
Bernal GM, Peterson DA: Neural stem cells as therapeutic agents for age-related brain repair. Aging Cell. 2004, 3 (6): 345-351. 10.1111/j.1474-9728.2004.00132.x.
Patarca-Montero R, Klimas NG, Fletcher MA: Immunotherapy of chronic fatigue syndrome: Therapeutic interventions aimed at modulating the Th1/Th2 cytokine expression balance. Journal of Chronic Fatigue Syndrome. 2001, 8 (1): 3-37. 10.1300/J092v08n01_02.
Nijs J, Nicolson GL, De Becker P, Coomans D, De Meirleir K: High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients. FEMS Immunology and Medical Microbiology. 2002, 34 (3): 209-214. 10.1111/j.1574-695X.2002.tb00626.x.
Nicolson GL, Gan R, Haier J: Evidence for Brucella spp. and Mycoplasma spp. co-infections in blood of chronic fatigue syndrome patients. Journal of Chronic Fatigue Syndrome. 2004, 12 (2): 5-17. 10.1300/J092v12n02_02.
Nicolson GL, Gan R, Haier J: Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: Association with signs and symptoms. APMIS. 2003, 111 (5): 557-566. 10.1034/j.1600-0463.2003.1110504.x.
Carlo-Stella N, Badulli C, De Silvestri A, Bazzichi L, Martinetti M, Lorusso L, Bombardieri S, Salvaneschi L, Cuccia M: A first study of cytokine genomic polymorphisms in CFS: Positive association of TNF-857 and IFNgamma 874 rare alleles. Clinical and Experimental Rheumatology. 2006, 24 (2): 179-182.
Vernon SD, Reeves WC: The challenge of integrating disparate high-content data: Epidemiological, clinical and laboratory data collected during an in-hospital study of chronic fatigue syndrome. Pharmacogenomics. 2006, 7 (3): 345-354. 10.2217/146224184.108.40.2065.
Cameron B, Bharadwaj M, Burrows J, Fazou C, Wakefield D, Hickie I, Ffrench R, Khanna R, Lloyd A: Prolonged illness after infectious mononucleosis is associated with altered immunity but not with increased viral load. Journal of Infectious Diseases. 2006, 193 (5): 664-671. 10.1086/500248.
Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S: Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. Journal of Internal Medicine. 2005, 257 (3): 299-310. 10.1111/j.1365-2796.2005.01452.x.
Richards RS, Roberts TK, Mathers D, Dunstan RH, McGregor NR, Butt HL: Investigation of erythrocyte oxidative damage in rheumatoid arthritis and chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome. 2000, 6 (1): 37-46. 10.1300/J092v06n01_04.
Puri BK: Proton and 31-phosphorus neurospectroscopy in the study of membrane phospholipids and fatty acid intervention in schizophrenia, depression, chronic fatigue syndrome (myalgic encephalomyelitis) and dyslexia. International Review of Psychiatry. 2006, 18 (2): 145-147. 10.1080/09540260600581852.
Jones JF: Defining CFS/ME: a novel approach to CFS. The seventh international conference on chronic fatigue syndrome and fibromyalgia; Madison, WI, USA. 2004
Vernon SD, Whistler T, Cameron B, Hickie IB, Reeves WC, Lloyd A: Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus. BMC Infectious Diseases. 2006, 6 (-): 7p-
De Meirleir K, Bisbal C, Campine I, De Becker P, Salehzada T, Demettre E, Lebleu B: A 37 kDa 2-5A binding protein as a potential biochemical marker for chronic fatigue syndrome. American Journal of Medicine. 2000, 108 (2): 99-105. 10.1016/S0002-9343(99)00300-9.
De Becker P, Englebienne P, Herst CV, De Meirleir K: Elastase activity response to antibiotic therapy in CFS patients - preliminary results. 2005
Nijs J, Meeus M, McGregor NR, Meeusen R, De Schutter G, Van Hoof E, de Meirleir K: Chronic fatigue syndrome: exercise performance related to immune function. Medicine and Science in Sports and Exercise. 2005, 37 (10): 1647 -11654. 10.1249/01.mss.0000181680.35503.ce.
Peterson D, Atwell L, Henry B, Knox K, Carrigan D: HHV-6A encephalopathy in patients with disabling fatigue. International conference on fatigue science; Karuizawa, Japan. 2005
Vermeulen RCW, Kurk RM, Scholte HR: Drug trials in CFS. International conference on fatigue science; Karuizawa, Japan. 2005
Bentler SE, Hartz AJ, Kuhn EM: Prospective observational study of treatments for unexplained chronic fatigue. Journal of Clinical Psychiatry. 2005, 66 (5): 625-632.
Fernandez AD, Elmore MK, Metzger DW: Azithromycin modulates murine immune responses to pneumococcal conjugate vaccine and inhibits nasal clearance of bacteria. Journal of Infectious Diseases. 2004, 190 (10): 1762-1766. 10.1086/425038.
Tsai WC, Rodriguez ML, Young KS, Deng JC, Thannickal VJ, Tateda K, Hershenson MB, Standiford TJ: Azithromycin blocks neutrophil recruitment in Pseudomonas endobronchial infection. American Journal of Respiratory and Critical Care Medicine. 2004, 170 (12): 1331-1339. 10.1164/rccm.200402-200OC.
Shinkai M, Chanf SP, Rubin BK: Immunomodulatory effects of macrolide antibiotics. Clinical Pulmonary Medicine. 2005, 12 (6): 341-348. 10.1097/01.cpm.0000187294.53696.c0.
Chia JKS, Chia LY: Chronic Chlamydia pneumoniae infection: A treatable cause of chronic fatigue syndrome. Clinical Infectious Diseases. 1999, 29 (2): 452-453.
Equi A, Balfour-Lynn IM, Bush A, Rosenthal M: Long term azithromycin in children with cystic fibrosis: A randomised, placebo-controlled crossover trial. Lancet. 2002, 360 (9338): 978-984. 10.1016/S0140-6736(02)11081-6.
Bell SC, Senini SL, McCormack JG: Macrolides in cystic fibrosis. Chronic Respiratory Disease. 2005, 2 (2): 85-98. 10.1191/1479972305cd066rs.
Nicolson GL, Marwan Y, Nasralla N, Nicolson L: The pathogenesis and treatment of mycoplasmal infections. Antimicrobics and Infectious Disease Newsletter (Elsevier Science). 1999, 17: 81-88. 10.1016/S1069-417X(00)88885-8.
Ridsdale L, Godfrey E, Chalder T, Seed P, King M, Wallace P, Wessely S: Chronic fatigue in general practice: Is counselling as good as cognitive behaviour therapy? A UK randomised trial. British Journal of General Practice. 2001, 51 (462): 19-24.
Plioplys AV, Plioplys S: Amantadine and L-Carnitine treatment of chronic fatigue syndrome. Neuropsychobiology. 1997, 35 (1): 16-23.
Vermeulen RCW, Scholte HR: Exploratory Open Label, Randomized Study of Acetyl- and Propionylcarnitine in Chronic Fatigue Syndrome. Psychosomatic Medicine. 2004, 66 (2): 276-282. 10.1097/01.psy.0000116249.60477.e9.
Bruce B, Fries JF: The Stanford Health Assessment Questionnaire: Dimensions and practical applications. Health and Quality of Life Outcomes. 2003, 1 (-): 6p-
Smets EMA, Garssen B, Bonke B, De Haes JCJM: The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. Journal of Psychosomatic Research. 1995, 39 (3): 315-325. 10.1016/0022-3999(94)00125-O.
Van Der Kloot WA, Oostendorp RAB, Van Der Meij J, Van Den Heuvel J: The Dutch version of the McGill pain questionnaire: A reliable instrument. Nederlands Tijdschrift voor Geneeskunde. 1995, 139 (13): 669-673.
Terluin B, Van Rhenen W, Schaufeli WB, De Haan M: The four-dimensional symptom questionnaire (4DSQ): Measuring distress and other mental health problems in a working population. Work and Stress. 2004, 18 (3): 187-207. 10.1080/0267837042000297535.
Wagner D, Nisenbaum R, Heim C, Jones JF, Unger ER, Reeves WC: Psychometric properties of the CDC Symptom Inventory for assessment of Chronic Fatigue Syndrome. Population Health Metrics. 2005, 3 (-): 8p-10.1186/1478-7954-3-8.
Vreken P, Van Lint AEM, Bootsma AH, Overmars H, Wanders RJA, Van Gennip AH: Rapid diagnosis of organic acidemias and fatty-acid oxidation defects by quantitative electrospray tandem-MS acyl-carnitine analysis in plasma. Advances in Experimental Medicine and Biology. 2000, 466 (-): 327-337.
Cho HJ, Hotopf M, Wessely S: The Placebo Response in the Treatment of Chronic Fatigue Syndrome: A Systematic Review and Meta-Analysis . Psychosomatic Medicine. 2005, 67 (2): 301-313. 10.1097/01.psy.0000156969.76986.e0.
Calo LA, Pagnin E, Davis PA, Semplicini A, Nicolai R, Calvani M, Pessina AC: Antioxidant effect of L-carnitine and its short chain esters: Relevance for the protection from oxidative stress related cardiovascular damage. International Journal of Cardiology. 2006, 107 (1): 54-60. 10.1016/j.ijcard.2005.02.053.
Kuratsune H, Yamaguti K, Lindh G, Evengard B, Takahashi M, Machii T, Matsumura K, Takaishi J, Kawata S, Langstrom B, Kanakura Y, Kitani T, Watanabe Y: Low levels of serum acylcarnitine in chronic fatigue syndrome and chronic hepatitis type C, but not seen in other diseases. INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE. 1998, 2 (1): 51-56.
Kuratsune H, Yamaguti K, Takahashi M, Misaki H, Tagawa S, Kitani T: Acylcarnitine deficiency in chronic fatigue syndrome. Clinical Infectious Diseases. 1994, 18 (SUPPL. 1): S62-S67.
Jones MG, Goodwin CS, Amjad S, Chalmers RA: Plasma and urinary carnitine and acylcarnitines in chronic fatigue syndrome. Clinica Chimica Acta. 2005, 360 (1-2): 173-177. 10.1016/j.cccn.2005.04.029.
Warren G, McKendrick M, Peet M: The role of essential fatty acids in chronic fatigue syndrome. A case- controlled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA. Acta Neurologica Scandinavica. 1999, 99 (2): 112-116.
Schultz MJ, Kesecioglu J, van der Poll T: Immunomodulating properties of macrolides: Animal and human studies. Current Medicinal Chemistry: Anti-Infective Agents. 2004, 3 (2): 101-107. 10.2174/1568012043353991.
Perry VH: The influence of systemic inflammation on inflammation in the brain: Implications for chronic neurodegenerative disease. Brain, Behavior, and Immunity. 2004, 18 (5): 407-413. 10.1016/j.bbi.2004.01.004.
The authors thank both the patients and the coworkers of the CFS Center Amsterdam for their indispensable help.
The author(s) declare that they have no competing interests.
The investigation was planned by and carried out under the clinical supervision of RCWV. HRS helped by interpretation and selection of the data, and correction of the manuscript.
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Vermeulen, R.C., Scholte, H.R. Azithromycin in Chronic Fatigue Syndrome (CFS), an analysis of clinical data. J Transl Med 4, 34 (2006). https://doi.org/10.1186/1479-5876-4-34
- Chronic Fatigue Syndrome
- Chronic Fatigue Syndrome Patient