The Journal of Headache and Pain

Official Journal of the "European Headache Federation" and of "Lifting The Burden - The Global Campaign against Headache"

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Association between Chlamydia pneumoniae IgG antibodies and migraine

The Journal of Headache and Pain200910:96

Received: 5 November 2008

Accepted: 6 January 2009

Published: 24 February 2009


In this study, there is a confirmed association between cerebral infarction with migraine and Chlamydia pneumoniae infection, but the association between C. pneumoniae IgG antibodies and migraine in the general population has not been investigated. C. pneumoniae IgG antibody levels were compared in 329 adult Chinese patients, who met the International Classification of Headache Disorders 2nd Edition (ICHD II) criteria for migraine, and in 329 healthy subjects. Factors such as gender, age, smoking, consumption of pickle, and body mass index were evaluated. One hundred and ninety-five (59.2%) migraine sufferers and 70 (21.27%) controls were C. pneumoniae IgG antibody-seropositive (P < 0.05). Based on a multivariate stepwise logistic model, the odds’ ratios for C. pneumoniae IgG antibody seropositivity, body mass index, smoking, and consumption of pickle were 3.397 (P = 0.000), 0.858 (P = 0.014), 1.692 (P = 0.012), and 5.469 (P = 0.0000), respectively. In conclusion, C. pneumoniae IgG antibodies may be a risk factor for migraine.


Chlamydia pneumoniae IgG antibodyMigraineImmunoglobulin


Migraine is a common type of headache with specific characteristics, including unilaterality, throbbing pain, photophobia or phonophobia, and nausea or vomiting [1]. Several large-scale epidemiological studies have revealed that the prevalence of migraine ranges from 6 to 13% in the general population [26].

Migraine is a recurrent neurovascular headache, but its mechanism is still unclear; it may be influenced by genetic, endocrine, neurological or immune mechanisms, as well as by other relevant factors. Headaches, in particular migraine, are known to be independent risk factors for ischemic stroke [413]. The association between migraine and stroke is more prominent in young women, particularly, in those taking oral contraceptives [811]. However, in middle aged and elderly adults of either sex, the association is controversial. Several epidemiological studies have indicated that severe headache and migraine should be considered as risk factors for future stroke, prior to the age of 70 [5, 12].

Chlamydia pneumoniae is an important pathogen in infections of the respiratory tract [13] and numerous reports have recently suggested its association with atherosclerosis. Infection of the vascular wall with C. pneumoniae has been linked to ischemic heart disease [1417] and stroke [1824] in epidemiological studies as well as in pathological studies using immunocytochemistry, polymerase chain reaction (PCR), and electron microscopy. In Japan, Miyashita et al. [25] reported a significant elevation in C. pneumoniae antibody levels in a patient with acute myocardial infarction and Kawamoto et al. [26] showed a significant relation between atherosclerotic lesions and common carotid arteries. Kawashima and Kawada [22] demonstrated a significant elevation of C. pneumoniae antibody levels in a patient with acute ischemic stroke.

A correlation between cerebral infarction with migraine and C. pneumoniae infection has been confirmed, but a correlation between C. pneumoniae IgG antibody levels and migraine has not been investigated in the general population. We therefore investigated this relationship between C. pneumoniae IgG antibodies and migraine.

Subjects and methods

Three hundred and twenty-nine Chinese patients attending our hospital out-patient department between September 2005 and December 2007 and who met the International Classification of Headache Disorders 2nd Edition (ICHD II) criteria for migraine were included in the study. There were 112 men and 217 women. Their ages ranged from 20 to 42 years (mean age 29.2 ± 8.2 years). Twenty patients had cerebellar atrophy, 30 had migraine with aura, 19 experienced bilateral pain, and 25 patients had relevant family histories. Ninety-one patients smoked (>5 years, >15 packs/month), 253 patients ate pickle (>3 years, >30 g/day). The average body mass index was 23.82 ± 1.56 kg/m2. The control group consisted of 329 healthy subjects, including 133 men and 196 women, aged between 20 and 44 years old (mean age 31.2 ± 9.2 years). Of these, 96 smoked, 103 ate salted, preserved foods, and the average body mass index was 23.81 ± 1.91 kg/m2. Individuals with recent histories of respiratory tract infections were excluded (Table 1).
Table 1

Demographic characteristics of migraine and control subjects


Control (N = 329)

Migraine (N = 329)

P value

Gender, male, N




Age (years)

29.2 ± 8.2

31.2 ± 9.2


Smoking, N (over 5 years, above 15 packs/month)




Pickle, N (over 3 years, above 30 g/day)




Body mass index (kg/m2)

23.82 ± 1.56

23.81 ± 1.91


Specimen collection

All blood samples were taken and separated in the morning.

Experimental methods

Infection was determined by measuring anti-C. pneumoniae IgG-specific antibody levels (Cp IgG index) using an enzyme-linked immunosorbent assay method (“HITAZYME C. pneumoniae”, Hitachi Chemical Co. Ltd., Tokyo, Japan). Levels were measured in serum from fasting blood, which had been preserved at −70°C. Levels below the 1.10 Cp IgG index were classified as seronegative and those above 1.10 as seropositive [27].

Statistical analysis

The results are shown as mean value ± standard deviation. The results were analyzed statistically using SPSS 10.0J (Statistical Package for Social Science Inc., Chicago, IL, USA) and compared using χ2 tests. A value of P < 0.05 was considered significant. The relationships between the presence of migraine and a positive Cp IgG index, gender (female 0; male 1), age, body mass index (BMI: body weight/height2), smoking, and consumption of pickle were examined by multiple logistic regression analysis.


One hundred and ninety-five (59.2%) migraine patients and 70 (21.27%) controls were Cp IgG antibody-seropositive. Based on multivariate stepwise logistic regression analysis, the odds’ ratios for C. pneumoniae IgG antibody positivity, body mass index, smoking, and consumption of pickle were 3.397 (95% CI: 2.395–4.817, P = 0.000), 0.858 (95% CI: 0.760–0.969, P = 0.014), 1.692 (95% CI: 1.124–2.547, P = 0.012), and 5.469 (95% CI: 3.631–8.237, P = 0.0000), respectively (Tables 2, 3).
Table 2

Chlamydia pneumoniae IgG antibodies in patients and controls




Seropositivity rates (%)

Study group




Control group




Migraine group compared with control group: χ2 = 98.7205, P < 0.005

Table 3

Relation between migraine and C. pneumoniae IgG antibodies as determined by multiple regression analysis logistic

Study factor






95% CI

Body mass index (kg/m2)







Smoking, N (%) (>5 years, >15 packs/month)







Pickle (>3 years, >30 g/day)







C. pneumoniae IgG







For each additional unit of body weight index, the risk of an occurrence of migraine increases 0.166 times; risk for the smokers who are likely to suffer from migraine is 1.692 times that of non-smokers; the risk for the people who are fond of pickle is 5.469 times than that of the group who prefer for fresh vegetables; the risk of the Cp-positive persons is 3.397 times than that of the Cp-negative


Migraine is a debilitating recurrent primary headache disorder, but its pathogenesis is still unclear. Migraine headaches have a complex pathophysiology and both vascular and neural theories have been proposed. One hypothesis suggests that the process begins with a series of destabilizing events within the brain that trigger cortical spreading depression (CSD) [28]. CSD can cause both migraine aura and trigeminal activation, which, in turn, promotes neuropeptide release and triggers peripheral and central mechanisms that promote headache and autonomic activation. Susceptibility to CSD and to migraine is, in part, genetically determined. The best evidence to date comes from certain subtypes of migraine with aura, in which, point mutations in genes controlling the translocation of calcium, sodium and potassium have been implicated. When the dura mater cranial vascular wall by stimulating the trigeminal nerve endings, vasoactive peptide substances such as substance P, calcitonin gene-related peptide, and neurokinin are released [29, 30], causing neurogenic inflammation. Even minor chemical or mechanical stimulation of the sensitized trigeminal nerve also causes excessive excitement. Injury receptors at trigeminal nerve endings can stimulate the trigeminal nerve, thereby causing headache, activating the autonomic nervous system, and giving rise to symptoms such as nausea and vomiting. Trigeminal nerve inflammation and allergic trigeminal nerve provide a theoretical basis for migraine [31, 32]. C. pneumoniae IgG antibody production following infection can lead to inflammation and sensitization of the trigeminal nerve, so leading to migraine attack.

The results of this study showed that 195 (59.2%) migraine patients and 70 (21.27%) controls were C. pneumoniae antibody-seropositive, while Nabipour et al. found a seropositivity rate of 37.7% in healthy humans. The discrepancy between these results could be related to differences in case selection, the number of cases, or to regional differences [33].


The results of this study suggest that there is a correlation between C. pneumoniae IgG antibodies and migraine. It is possible that C. pneumoniae IgG antibodies may damage the brain vasculature, promote atherosclerosis and disrupt endothelial cell function, thereby stimulating vasospasm and damaging the blood–brain barrier. Changes in the environment can also stimulate a migraine attack due to the inflammation and sensitization of the trigeminal nerve caused directly by C. pneumoniae IgG antibodies.



This work was supported by Hubei province health department.

Conflict of interest


Authors’ Affiliations

Department of Neurology, The Central Hospital in En Shi, En Shi, People’s Republic of China
Department of Neurology, Tong ji Hospital, Tong ji Medical College, Hua Zhong University of Science and Technology, Wuhan, People’s Republic of China


  1. Headache Classification Committee of the International Headache Society (2004) The international classification of headache disorders. Cephalalgia 24:1–160Google Scholar
  2. Scher AI, Terwindt GM, Picavet HS, Verschuren WM, Ferrari MD, Launer LJ (2005) Cardiovascular risk factors and migraine: the GEM population-based study. Neurology 64:614–620View ArticlePubMedGoogle Scholar
  3. Takeshima T, Ishizaki K, Fukuhara Y et al (2004) Population based door-to-door survey of migraine in Japan: the Daisen study. Headache 44:8–19View ArticlePubMedGoogle Scholar
  4. Kurth T, Slomke MA, Kase CS et al (2005) Migraine, headache, and the risk of stroke in women: a prospective study. Neurology 64:1020–1026View ArticlePubMedGoogle Scholar
  5. Merikangas KR, Fenton BT, Cheng SH, Stolar MJ, Risch N (1997) Association between migraine and stroke in a large-scale epidemiological study of the United States. Arch Neurol 54:362–368View ArticlePubMedGoogle Scholar
  6. Stang PE, Carson AP, Rose KM et al (2005) Headache, cerebrovascular symptoms, and stroke: the Atherosclerosis Risk in Communities Study. Neurology 64:1573–1577View ArticlePubMedGoogle Scholar
  7. Tzourio C, Iglesias S, Hubert JB et al (1993) Migraine and risk of ischaemic stroke: a case–control study. BMJ 307:289–292PubMed CentralView ArticlePubMedGoogle Scholar
  8. Etminan M, Takkouche B, Isorna FC, Samii A (2005) Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 330:63–65PubMed CentralView ArticlePubMedGoogle Scholar
  9. Carolei A, Marini C, De Matteis G, The Italian National Research Council Study Group on Stroke in the Young (1996) History of migraine and risk of cerebral ischaemia in young adults. Lancet 347:1503–1506View ArticlePubMedGoogle Scholar
  10. Tzourio C, Tehindrazanarivelo A, Iglesias S et al (1995) Case control study of migraine and risk of ischaemic stroke in young women. BMJ 310:830–833PubMed CentralView ArticlePubMedGoogle Scholar
  11. Chang CL, Donaghy M, Poulter N (1999) Migraine and stroke in young women: case–control study. The World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. BMJ 318:13–18PubMed CentralView ArticlePubMedGoogle Scholar
  12. Jousilahti P, Tuomilehto J, Rastenyte D, Vartiainen E (2003) Headache and the risk of stroke: a prospective observational cohort study among 35,056 Finnish men and women. Arch Intern Med 163:1058–1062View ArticlePubMedGoogle Scholar
  13. Grayston JT, Campbell LA, Kuo CC et al (1990) A new respiratory pathogen: Chlamydia pneumoniae strain TWAR. J Infect Dis 161:618–625View ArticlePubMedGoogle Scholar
  14. Saikku P, Leinonen M, Mattila K et al (1988) Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 2:983–986View ArticlePubMedGoogle Scholar
  15. Shor A, Kuo CC, Patton DL (1992) Detection of Chlamydia pneumoniae in coronary arterial fatty streaks and atheromatous plaques. S Afr Med J 82:158–161PubMedGoogle Scholar
  16. Kuo CC, Shor A, Campbell LA, Fukushi H, Patton DL, Grayston JT (1993) Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries. J Infect Dis 167:841–849View ArticlePubMedGoogle Scholar
  17. Halvorsen DS, Borvik T, Njolstad I, Gutteberg TJ, Vorland LH, Hansen JB (2002) Chlamydia pneumoniae IgA- and IgG antibodies in young survivors of myocardial infarction. A comparison of antibody detection by a microimmunofluorescence test and an enzyme immunoassay. J Intern Med 251:142–147View ArticlePubMedGoogle Scholar
  18. Cook PJ, Honeybourne D, Lip GYH, Beevers DG, Wise R, Davies P (1998) Chlamydia pneumoniae antibody titers are significantly associated with acute stroke and transient cerebral ischemia: the West Birmingham Stroke Project. Stroke 29:404–410View ArticlePubMedGoogle Scholar
  19. Wimmer ML, Sandmann-Strupp R, Saikku P, Haberl RL (1996) Association of chlamydial infection with cerebrovascular disease. Stroke 27:2207–2210View ArticlePubMedGoogle Scholar
  20. Fagerberg B, Gnarpe J, Gnarpe H, Agewall S, Wikstrand J (1999) Chlamydia pneumoniae but not cytomegalovirus antibodies are associated with future risk of stroke and cardiovascular disease: a prospective study in middle-aged to elderly men with treated hypertension. Stroke 30:299–305View ArticlePubMedGoogle Scholar
  21. Elkind MS, Lin IF, Grayston JT, Sacco RL (2000) Chlamydia pneumoniae and the risk of first ischemic stroke: the Northern Manhattan Stroke Study. Stroke 31:1521–1525View ArticlePubMedGoogle Scholar
  22. Kawashima N, Kawada J (2000) Chlamydia pneumoniae antibody titers in patients with acute ischemic stroke. Rinsho Shinkeigaku 40:1063–1068 (in Japanese, abstract in English)PubMedGoogle Scholar
  23. Virok D, Kis Z, Karai L et al (2001) Chlamydia pneumoniae in atherosclerotic middle cerebral artery. Stroke 32:1973–1978View ArticlePubMedGoogle Scholar
  24. Madre JG, Garcia JL, Gonzalez RC et al (2002) Association between seropositivity to Chlamydia pneumoniae and acute ischaemic stroke. Eur J Neurol 9:303–306View ArticlePubMedGoogle Scholar
  25. Miyashita N, Toyota E, Sawayama T, Matsushima T (1998) An association of an antibody against Chlamydia pneumoniae and coronary heart disease observed in Japan. Eur Heart J 19:971 (letter)View ArticlePubMedGoogle Scholar
  26. Kawamoto R, Doi T, Tokunaga H, Konishi I (2001) An association between an antibody against Chlamydia pneumoniae and common carotid atherosclerosis. Intern Med 40:208–213View ArticlePubMedGoogle Scholar
  27. Kishimoto T, Matsushima T, Morikawa T, Kawagoe K (1999) Assay of specific anti-Chlamydia pneumoniae antibodies by ELISA method. 3. Setting of serological criteria. Kansensyogaku Zasshi 73:457–466 (in Japanese, abstract in English)View ArticleGoogle Scholar
  28. Dalkara T, Zervas NT, Moskowitz MA (2006) From spreading depression to the trigeminovascular system. Neurol Sci 27(Suppl 2):S86–S90View ArticlePubMedGoogle Scholar
  29. Moskowitz MA (1990) Basic mechanisms in vascular headache. Neurol Clin North Am 8:801–815Google Scholar
  30. Sarchielli P, Alberti A, Codini M et al (2000) Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. Cephalalgia 20:907–918View ArticlePubMedGoogle Scholar
  31. Kaube H, Katsarava Z, Przywara S et al (2002) Acute migraine headache: possible sensitization of neurons in the spinal trigeminal nucleus? Neurology 58:1234–1238View ArticlePubMedGoogle Scholar
  32. Cao Y, Welch KMA, Aurora S et al (1999) Functional MRI-BOLD of visually triggered headache in patients with migraine. Arch Neurol 56:548–554View ArticlePubMedGoogle Scholar
  33. Nabipour I, Vahdat K, Jafari SM, Amiri M, Shafeiae E, Riazi A, Amini AL, Sanjdideh Z (2007) Correlation of hyperhomocysteinaemia and chlamydia pneumoniae IgG seropositivity with coronary artery disease in a general population. Heart Lung Circ 16(6):416–422View ArticlePubMedGoogle Scholar


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