Varicella Zoster is the Cause of Giant Cell Arteritis

vzv and gcaBackground

Giant cell arteritis is an inflammatory condition of certain blood vessels that presents in the elderly. Those vessels affected include the:

  • temporal artery resulting in headache and scalp tenderness over the inflamed artery,
  • ciliary artery resulting in ischaemic optic neuropathy,
  • retinal artery resulting in central retinal artery occlusion,
  • arteries to various muscles resulting in jaw claudication and polymyalgia rheumatica.

There may be systemic symptoms of weight loss and fever, and a raised eosinophil sedimentation rate is typical. The main clinical urgency relates to the visual loss, as this may be permanent without prompt treatment with high dose steroids.

Varicella zoster reactivation later in life following initial infection with chicken pox typically results in shingles, but a recognised complication of shingles is an arteritis of large vessels such as the carotid artery. This may result in emboli and consequently present as stroke.

Since both arteritides occur in similar populations, it was natural to speculate that there might be some pathogenic link. However different pathological studies on temporal arteries have yielded different results. Some revealed no VZV on Polymerase chain reaction (PCR) or immunohistochemistry (IHC), while other series have revealed around 25% occurrence in GCA positive biopsy samples , and 0% in GCA negative samples.

This paper, Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis in Neurology (2015) by Gilden and a large number of co-authors from all the different centres that contributed temporal arteries, addresses this question with a rigorous examination for the correlation of CGA findings and VZV presence in alternating contiguous temporal artery slices and uses temporal arteries of cadavers as controls.

Study Design and Findings

All investigators took formalin fixed temporal arteries and made 100 5-micron sections. Every other section was examined by IHC for VZV antigen and, in one case, electron microscopy (EM) for virions. If the antigen test was positive, PCR was performed for viral DNA. The remaining sections were examined for GCA inflammation changes. To validate the sensitivity, positive controls were obtained by infecting cadaveric temporal arteries and testing after 14 days in vitro.

A total of 86 histologically confirmed GCA positive temporal arteries were examined, and 16 negative post-mortem controls (i.e. randomly selected, not the ones that were deliberately infected) . All subjects had to be over 50 years. There were no other clinical inclusion or exclusion criteria, but if they were having biopsies presumably the patients had clinical features leading to suspicion of GCA. There was disagreement over the blinded light microscopy findings for GCA in 4 of the presumed positive cases and 3 of the negative controls, so these were removed from analysis. (The findings in these should really have been included in the results; if three additional negative controls out of sixteen all had GCA changes and then analysed and found to have VZV, this would have changed the results in a major way! Presumably at least one pathologist thought they had GCA changes; is this a common coincidental finding?)

VZV was present in 74% of the GCA cases and in one of the cadaveric negative controls. The VZV was present usually in multiple slices with intervening negative areas (skip lesions). Across all 61 VZV positive samples, there were 347 VZV positive skip lesions. The virus tended to be present more in the adventitia than in the intima, and was sometimes present in adjoining skeletal muscle.

In one positive case, VZV virions were found on EM in the artery adventitia.

Only in some cases was PCR positive, perhaps due to the formalin fixation technique.

In 89% of cases where there was VZV antigen, there were light microscopy changes of GCA in adjacent sections. (Presumably, in the remaining cases the light microscopy changes were only in distant sections. If they were not positive somewhere they would not have been included in the study.) In the only post mortem sample out of 13 that had positive VZV there were no GCA changes.

The authors conclude a causative relationship on the basis of:

  • The pattern of VZV presence is patchy (ie skip lesions) in the same way that the typical GCA pattern is patchy.
  • The pattern of VZV was such that there were often GCA changes in nearby sections.
  • The VZV was present in adjoining skeletal muscles, the increased incidence in the adventitia and presence of virions in one case indicating a spread starting outside the artery wall from the cranial nerve ganglia (presumably via the nerve supply to the vessels).
  • The authors never find in other diseases, e.g. meningitis, that inflammation per se is responsible for VZV activation.
  • The pathology and distribution of VZV in these samples is similar to that in other cases of VZV vasculopathy not considered to be GCA.

The authors consider that the variable findings in the literature reflect the fact that the other studies did not take enough sections – the skip lesion problem. Relying on PCR might also result in negative findings. They predict that if they took hundreds of sections per biopsy they would have found VZV in all GCA positive cases, in other words VZV reactivation is the sole cause of GCA.

The obvious implication is that while steroids may suppress the inflammatory response of GCA, such treatment often needs to be maintained for a long time and some cases are refractory. Possibly the steroids are also prolonging the viral activation. Hence aciclivor should be added to the treatment regime.


The journal club were persuaded by the main finding and will be prescribing iv acyclovir in future. Consideration might be given to gancyclovir since the effectiveness of acyclovir is less against VZV than against HSV. Hence we would not rely on oral acyclovir.

Points that were noted included the fact that the authors could have made more of the presence or absence of section-by-section concordance vs discordance regarding VZV and GCA pathology. It is one thing to say that the GCA changes were more likely in sections near VZV presence, but perhaps as important to find a concordant absence of both changes between the skip lesions. This could be tested statistically.

Comment was made about the post-mortem specimens. Might the VZV antigen degrade after death? What was the time between death and fixing the temporal artery?

The reason for choosing post mortem controls is obvious. If there was a negative living control, it would be wondered why they were having the biopsy in the first place. Did they really indeed have mild GCA? However, in our experience there are plenty of TA negative biopsies because the disease is over-diagnosed clinically. If the same rigour of analysing multiple sections was employed, the negative presence of VZV in living tissue in a GCA susceptible population would have been persuasive.

Clearly a study comparing these pathological findings with clinical features and outcome is the next step. However, after reading this study, we would be a little worried ethically about not adding antiviral treatment in a placebo arm of a future controlled trial. The level of evidence ends up being inversely correlated with the likely effectiveness of an intervention!

This paper was presented to our Journal Club by Dr Tim Ham, Specialist Registrar in Neurology, Queens Hospital, Romford, UK.


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