C pneumoniae is Implicated in Giant Cell Arteritis

and Acute Anterior Uveitis

Giant cell arteritis is an inflammation of the medium and large-sized arteries, mainly of the outermost of their three layers, the adventitia. It is known to be associated with previous upper respiratory tract symptoms. The occurrence of cases is often clustered in certain time periods and geographic locations. It is primarily a disease of the elderly, and is more common in women than in men. Fever of unknown origin is one of the symptoms. Along with polymyalgia rheumatica, a related clinical syndrome, it is strongly associated with DR4 positivity. (187360 TEMPORAL ARTERITIS Alternative titles; symbols GIANT CELL ARTERITIS; GCA; CRANIAL ARTERITIS; POLYMYALGIA RHEUMATICA. OMIM; HLA-DRB1 allele distribution in polymyalgia rheumatica and giant cell arteritis: influence on clinical subgroups and prognosis. VM Martínez-Taboda, MJ Bartolome, M Lopez-Hoyos, R Blanco, C Mata, J Calvo, A Corrales, V Rodriguez-Valverde. Semin Arthritis Rheum 2004 Aug;34(1):454-464.)

TEMPORAL ARTERITIS / OMIM
Martínez-Taboda - Semin Arthritis Rheum 2004 abstract / PubMed

Detection of Chlamydia pneumoniae in giant cell vasculitis and correlation with the topographic arrangement of tissue-infiltrating dendritic cells. AD Wagner, HC Gerard, T Fresemann, WA Schmidt, E Gromnica-Ihle, AP Hudson, H Zeidler. Arthritis and Rheumatism 2000 Jul;43(7):1543-1551. 8 of 9 GCA patients were PCR-positive for Chlamydia pneumoniae, while the only one of nine controls who was positive for CP had respiratory symptoms. In some of the tissue specimens, CP was found outside of cells, "possibly suggesting that the organism was viable and undergoing active vegetative growth in temporal artery tissues in GCA patients."

Wagner - Arthritis & Rheumatism 2000 abstract / PubMed
Wagner / Medscape 2000 news

Temporal arteritis associated with Chlamydia pneumoniae DNA detected in an artery specimen. G Haugeberg, R Bie, SA Nordbo. J Rheumatol 2001 Jul;28(7):1738-1739. Letter; no abstract.

Haugeberg - J Rheumatol 2001 abstract / PubMed

Temporal arteritis and Chlamydia pneumoniae: failure to detect the organism by polymerase chain reaction in ninety cases and ninety controls. RJ Regan, BJ Wood, YH Hsieh, ML Theodore, TC Quinn, DB Hellmann, WR Green, CA Gaydos, JH Stone. Arthritis Rheum 2002 Apr;46(4):1056-1060. 90 TA biopsies versus 90 controls. "Using the CP1-CP2/CPC-CPD primer set, only 1 TA case sample (1% of all case samples) was positive for the ompA gene. One control sample was also positive using these primers. With the Cpn90/Cpn91 primers, none of the cases and none of the controls were positive for the 16S rRNA gene."

Regan - Arthritis Rheum 2002 abstract / PubMed

No evidence of parvovirus B19, Chlamydia pneumoniae or human herpes virus infection in temporal artery biopsies in patients with giant cell arteritis. J Helweg-Larsen, B Tarp, N Obel, B Baslund. Rheumatology (Oxford) 2002 Apr;41(4):445-449. "Thirteen patients had classical GCA, two had biopsy-negative GCA, 10 patients had polymyalgia rheumatica and five patients had other conditions... In all 30 biopsies, PCR was negative for DNAs of parvovirus B19, each of the eight human herpes viruses and C. pneumoniae."

Helweg-Larsen - Rheumatology (Oxford) 2002 abstract / PubMed

Is giant cell arteritis an infectious disease? Biological and epidemiological evidence. P Duhaut, S Bosshard, JP Ducroix. Presse Med 2004 Nov 6;33(19 Pt 2):1403-1408. Review.

Duhaut - Presse Med 2004 abstract / PubMed

Infection and temporal arteritis: a PCR-based study to detect pathogens in temporal artery biopsy specimens. RJ Cooper, S D'Arcy, M Kirby, M Al-Buhtori, MJ Rahman, L Proctor, RE Bonshek. J Med Virol 2008 Mar;80(3):501-505. "Samples from 37 temporal artery biopsies with histological evidence of arteritis and 66 samples from histologically negative temporal artery biopsies, all from different patients, were negative for C. pneumoniae, HSV, VZV, EBV, and HHV7 DNA. Two of the 37 histologically positive specimens were positive for HHV6, another two for CMV and a further two for parvovirus B19 DNA. Parvovirus B19 DNA was also detected in five histologically negative biopsies, one positive for HCMV DNA and a further one was positive for HHV6 DNA. There is no statistically significant difference to the presence of virus DNA in the two types of specimens (P = 0.538)."

Cooper - J Med Virol 2008 abstract / PubMed

Serum levels of antibodies to Chlamydia pneumoniae and human HSP60 in giant cell arteritis patients. M López-Hoyos, L Alvarez, M Ruiz Soto, R Blanco, M José Bartolomé, VM Martínez-Taboada. Clin Exp Rheumatol 2008 Nov-Dec;26(6):1107-1110. "17 GCA patients, 39 polymyalgia rheumatica (PMR) patients and 23 age-matched healthy subjects.RESULTS:Serum IgG anti-hHSP60, but not anti-C. pneumoniae, antibodies were significantly increased in GCA patients in comparison with PMR patients or healthy controls. After steroid therapy, both anti-hHSP60 and -C. pneumoniae antibodies decreased significantly in both groups of patients."

López-Hoyos - Clin Exp Rheumatol 2008 abstract / PubMed

Acute Chlamydia pneumoniae infection in the pathogenesis of autoimmune diseases. M Fujita, S Hatachi, M Yagita. Lupus 2009 Feb;18(2):164-168. 82 patients with several autoimmune diseases and 70 controls. "Chlamydia pneumoniae IgM positive cases were more frequent among the patients with rheumatoid arthritis (RA; 30%, P < 0.05), systemic lupus erythematosus (SLE; 28.0%, P < 0.05), dermatomyositis/polymyositis (23%, NS), myeloperoxidase-antineutrophil cytoplasmic autoantibody (MPO-ANCA)-associated vasculitis (33%, NS), adult onset of Still's disease (29%, NS) and giant cell arteritis/Takayasu arteritis (50%, NS) than among the controls. This positive frequency was statistically significant in RA and SLE."

Fujita - Lupus 2009 abstract / PubMed

No Correlation Between Giant Cell Arteritis and Chlamydia pneumoniae Infection: Investigation of 189 Patients With Standard and Improved PCR Methods. F Njau, T Ness, U Wittkop, T Pancratz, M Eickhoff, AP Hudson, H Haller, AD Wagner. J Clin Microbiol 2009 Jun;47(6):1899-901. "189 temporal artery biopsies from giant cell arteritis (GCA) patients were investigated using sensitive PCR targeting Chlamydia pneumoniae. Chlamydial DNA was detected in 17 samples, 11/17 were positive for chlamydial antigen."

Njau - J Clin Microbiol 2009 abstract / PubMed
Njau - J Clin Microbiol 2009 full article / PubMed Central

Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis. D Gilden, T White, N Khmeleva, A Heintzman, A Choe, PJ Boyer, C Grose, JE Carpenter, A Rempel, N Bos, B Kandasamy, K Lear-Kaul, DB Holmes, JL Bennett, RJ Cohrs, R Mahalingam, N Mandava, CG Eberhart, B Bockelman, RJ Poppiti, MA Tamhankar, F Fogt, M Amato, E Wood, V Durairaj, S Rasmussen, V Petursdottir, L Pollak, S Mendlovic, D Chatelain, K Keyvani, W Brueck, MA Nagel. Neurology 2015 Feb 18 [Epub ahead of print]. By IHC and PCR. "VZV antigen was found in 61/82 (74%) GCA-positive TAs compared with 1/13 (8%) normal TAs (p < 0.0001, relative risk 9.67, 95% confidence interval 1.46, 63.69). Most GCA-positive TAs contained viral antigen in skip areas. VZV antigen was present mostly in adventitia, followed by media and intima. VZV antigen was found in 12/32 (38%) skeletal muscles adjacent to VZV antigen-positive TAs. Despite formalin fixation, VZV DNA was detected in 18/45 (40%) GCA-positive VZV antigen-positive TAs, in 6/10 (60%) VZV antigen-positive skeletal muscles, and in one VZV antigen-positive normal TA. Varicella-zoster virions were found in a GCA-positive TA. In sections adjacent to those containing VZV, GCA pathology was seen in 89% of GCA-positive TAs but in none of 18 adjacent sections from normal TAs."

Gilden - Neurology 2015 abstract / PubMed

[Re Gilden 2015] New Evidence of Varicella-Zoster in Giant Cell Arteritis. By Pauline Anderson. Medscape Medical News, Feb. 20, 2015. "'Our analysis, which is the largest to-date, provides compelling evidence that the virus also reactivates in people over 60 in another way, triggering giant cell arteritis,' said study author Don Gilden, MD,...VZV antigen was found in cells in the adventitia, media and intima of temporal arteries, consistent with the well-documented ability of VZV to replicate in all organs during disseminated varicella and zoster as well as in all human non-neuronal cells in tissue culture, they write... The presence of VZV antigen in GCA lesions is not likely a 'bystander effect' due to subclinical reactivation induced by inflammation, say the authors. 'After more than 3 decades of analysis of tissue sections for VZV from patients with inflammatory/infectious diseases, we found that while VZV causes inflammation, inflammation does not cause VZV to reactivate and infect the inflamed region.' Because multiple agents underlie other diseases (eg, pneumonia and meningitis), 'it remains possible that agents in addition to VZV cause GCA,' write the authors."

New Evidence of Varicella-Zoster in Giant Cell Arteritis / Medscape 2015

Autoimmunity Research Foundation

The Autoimmunity Research Foundation conducts research on the role of C. pneunoniae in sarcoidosis. Trevor G. Marshall, the Chairman, says that no single antibiotic among those cited for use against C. pneumoniae (Rifampin, Azithromycin, Gatifloxacin, and Clarithromycin) has any effect against these intra-phagocytic bacteria. (Rapid Response. Intra-mononuclear-cell Bacteria are Key to much Chronic Disease. GT Marshall. BMJ 2005 Aug. 12).

About Us / Autoimmunity Research Foundation
Marshall / BMJ 2005

Uveitis

"The most common form of uveitis is anterior uveitis, which involves inflammation in the front part of the eye. It is often called iritis because it is usually only effects the iris, the colored part of the eye. The inflammation may be associated with autoimmune diseases, but most cases occur in healthy people. The disorder may affect only one eye. It is most common in young and middle-aged people... Posterior uveitis affects the back part of the uvea, and involves primarily the choroid, a layer of blood vessels and connective tissue in the middle part of the eye. This type of uveitis is called choroiditis. If the retina is also involved it is called chorioretinitis..." (Medline Plus, accessed 3/6/10.) "Anterior uveitis is the most common form, and occurs annually at a frequency of about 8 to 15 cases per 100,000 people. This type of uveitis affects men and women equally... A California study estimated that more than 280,000 people in the United States are affected by uveitis each year, which is almost three times greater than previously thought. The study, based on medical records from six northern California communities, also estimated that uveitis is the reason for 30,000 new cases of blindness a year and up to 10 percent of all the cases of blindness." (Uveitis, Iritis and Eye Inflammation. By Gina White; updates by Marilyn Haddrill. About vision, accessed 3-6-10.)

Detection of serum antibodies to Chlamydia pneumoniae in patients with endogenous uveitis and acute conjunctivitis. K Numazaki, S Chiba, K Aoki, K Suzuki, S Ohno. Clin Infect Dis 1997 Oct;25:928-929. "We determined the titer of serum antibodies to C. pneumoniae for 48 adult patients with endogenous uveitis (29 had sarcoidosis, 10 had Behcet's disease, and 9 had Vogt-Kyanagi disease) and for 28 adult patients with acute conjunctivitis. We also determined the titer of serum antibodies to C. pneumoniae in 30 healthy adults who served as controls... Of 30 healthy adults, IgG antibodies to C. pneumoniae were detected in 17 (56.7%), and IgA antibodies were detected in 15 (50.0%). IgM antibodies to C. pneumoniae were detected in 6 (20%) adults. Of 29 patients with sarcoidosis, IgG antibodies to C. pneumoniae were detected in 21 (72.4%), and IgA antibodies were detected in 15 (51.7%); IgM antibodies to C. pneumoniae were detected in 17 (58.6%) patients. IgG antibodies to C. pneumoniae were detected in seven (70%) of 10 patients with Behcet's disease and in three (33%) of nine patients with Vogt-Koyanagi disease. Neither IgA nor IgM antibodies to C. pneumoniae were detected in the patients with Behcet's or Vogt-Koyanagi disease. Of 28 patients with acute conjunctivitis, IgG antibodies to C. pneumoniae were detected in 16 (57.1%); in 2 (7.1%) of these patients, IgA and IgM antibodies to C. pneumoniae were detected. The prevalence of serum IgA and IgM antibodies to C. pneumoniae in patients with endogenous uveitis associated with sarcoidosis was significantly higher than that in patients with other endogenous uveitis (P< 0.01; t-test; Welch's modification)."

Numazaki - Clin Infect Dis 1997 (no abstract) / PubMed

Chlamydial antibodies in patients with previous acute anterior uveitis. M Huhtinen, M Puolakkainen, K Laasila, M Sarvas, A Karma, M Leirisalo-Repo. Invest Ophthalmol Vis Sci 2001 Jul;42(8):1816-1819. 64 patients. "The prevalence of antibodies to C. pneumoniae (69% vs. 72%) and C. trachomatis (11% vs. 6%) did not differ significantly between the patients and control subjects, nor did the level of IgG antibodies to Cpn Hsp60 (median EIA unit, 65 vs. 48). The levels of IgA antibodies to Cpn Hsp60 were significantly higher in the patients with AAU than in the control subjects (median EIA unit, 18 vs. 10; two-tailed Wilcoxon signed rank test, P = 0.0001)."

Huhtinen - Invest Ophthalmol Vis Sci 2001 abstract / PubMed

Other Infections

Pattern of uveitis in a referral centre in Tunisia, North Africa. M Khairallah, SB Yahia, A Ladjimi, R Messaoud, S Zaouali, S Attia, S Jenzeri, B Jelliti. Eye (Lond) 2007 Jan;21(1):33-39. 472 patients. "The mean age at onset of uveitis was 34 years. The male-to-female ratio was 1:1.1. Uveitis was unilateral in 282 patients (59.7%) and bilateral in 190 patients (40.3%). Anterior uveitis was most common (166 patients; 35.2%), followed by posterior uveitis (133 patients; 28.2%), panuveitis (100 patients; 21.2%), and intermediate uveitis (73 patients; 15.5%). A specific diagnosis was found in 306 patients (64.8%). The most common cause of anterior uveitis was herpetic uveitis (56 patients; 33.7%). Toxoplasmosis was the most frequent cause of posterior uveitis (51 patients; 38.3%). Intermediate uveitis was most commonly idiopathic (63 patients; 86.3%). Behçet's disease was the most common cause of panuveitis (36 patients; 36%), followed by Vogt-Koyanagi-Harada (VKH) disease (15 patients; 15%)."

Khairallah - Eye (Lond) 2007 abstract / PubMed

High prevalence of fastidious bacteria in 1520 cases of uveitis of unknown etiology. M Drancourt, P Berger, C Terrada, B Bodaghi, J Conrath, D Raoult, P LeHoang. Medicine (Baltimore) 2008 May;87(3):167-176. 1321 patients; "infection was diagnosed in 147 (11.1%) patients: 78 (53%) were caused by fastidious bacteria that included spirochetes, Bartonella species, intracellular bacteria (Chlamydia species, Rickettsia species, Coxiella burnetii), and Tropheryma whipplei; 18 by herpes viruses; and 9 by fungi. Bartonella quintana, Coxiella burnetii, Paracoccus yeei, Aspergillus oryzae, and Cryptococcus albidus were found to be associated with uveitis for the first time, to our knowledge."

Drancourt - Medicine (Baltimore) 2008 abstract / PubMed

Use of multiplex PCR and real-time PCR to detect human herpes virus genome in ocular fluids of patients with uveitis. S Sugita, N Shimizu, K Watanabe, M Mizukami, T Morio, Y Sugamoto, M Mochizuki. Br J Ophthalmol 2008 Jul;92(7):928-932. 100 patients with uveitis and ocular lymphoma. "In all of the patients with acute retinal necrosis (n=16) that were tested, either the HSV1 (n=2), HSV2 (n=3), or VZV (n=11) genome was detected. In all patients, high copy numbers of the viral DNA were also noted, indicating the presence of viral replication. In another 10 patients with anterior uveitis with iris atrophy, the VZV genome was detected. When using multiplex PCR, EBV-DNA was detected in 19 of 111 samples (17%). However, real-time PCR analysis of EBV-DNA indicated that there were only six of the 19 samples that had significantly high copy numbers. The cytomegalovirus (CMV) genome was detected in three patients with anterior uveitis of immunocompetent patients and in one immunocompromised CMV retinitis patient. In addition, one patient with severe unilateral panuveitis had a high copy number of HHV6-DNA. There was no HHV7- or HHV8-DNA detected in any of the samples."

Sugita - Br J Ophthalmol 2008 full article / PubMed Central

Novel infectious agents causing uveitis. M Khairallah, SP Chee, SR Rathinam, S Attia, V Nadella. Int Ophthalmol 2010 Oct;30(5):465-483. "In any patient with uveitis, an infectious cause should be ruled out first. The differential diagnosis includes multiple well-known diseases including herpes, syphilis, toxoplasmosis, tuberculosis, bartonellosis, Lyme disease, and others. However, clinician should be aware of emerging infectious agents as potential causes of systemic illness and also intraocular inflammation," including Rickettsioses, West Nile virus infection, Rift valley fever, Dengue fever, and Chikungunya.

Khairallah - Int Ophthalmol 2010 abstract / PubMed

Uveitis- a rare disease often associated with systemic diseases and infections- a systematic review of 2619 patients. T Barisani-Asenbauer, SM Maca, L Mejdoubi, W Emminger, K Machold, H Auer. Orphanet J Rare Dis 2012 Aug 29;7(1):57. 2619 patients, 59.9% anterior, 14.8% intermediate, 18.3% posterior, and 7.0% from panuveitis. "37.2% of all cases showed an association between uveitis and extra-organ diseases; diseases with primarily arthritic manifestations were seen in 10.1% of all cases, non-infectious systemic diseases (i.e., Behcet's disease, sarcoidosis or multiple sclerosis) in 8.4% and infectious uveitis in 18.7%. 49.4% of subjects suffering from anterior uveitis tested positively for the HLA-B27 antigen. In posterior uveitis cases 29% were caused by ocular toxoplasmosis and 17.7% by multifocal choroiditis."

Barisani-Asenbauer - Orphanet J Rare Dis 2012 abstract / PubMed

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