Varicella Zoster Virus in Giant Cell Arteritis

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Overview / Synopsis: The aim of this intended research proposal is to explore the proposed link between varicella zoster virus infection and giant cell arteritis.

Primary human infection with varicella zoster virus results in chickenpox; prior to the introduction of the vaccine it was a common childhood illness (1), with seroprevalence greater than 90% before adolescence (2-4). The introduction of a safe and effective live attenuated vaccine in the late 1990’s has significantly reduced the incidence and severity of primary varicella infections (chickenpox) (5-8). Primary infection with varicella confers lifelong immunity to chickenpox (5) however it is known that the varicella zoster virus remains dormant within the central nervous system and may reactivate later in life as shingles (herpes zoster) (9, 10); with up to 50% of the population having had herpes zoster by age 85 (6).

Giant cell arteritis is the commonest form of large vessel vasculitis in older age (>65 years) (11); it is more common among Caucasian population of European origin (12) and has been demonstrated to be associated with polymyalgia rheumatica in up to 50% of confirmed GCA (13-15). Temporal arteritis is a specific variant of giant cell arteritis  resulting in scalp tenderness over the temple, jaw pain, vision changes (16); if left untreated permanent vision loss may result due to occlusion of the posterior ciliary artery (16). The mean age at diagnosis is 71 and 73 for men and women respectively, with a greater incidence in females greater than males (16).

The hypothesis has been made that the varicella zoster virus may play a role in the development of giant cell arteritis (17-20); however recent literature has been inconsistent with findings to support or reject this hypothesis (3, 11, 21, 22). This project seeks to identify the presence of varicella zoster virus within temporal artery biopsy samples with histopathologically confirmed giant cell arteritis. Subsequent two sample Chi-squared statistical analysis of the data aims to determine if there is a statistical significance in the rate of detection of varicella zoster within samples with confirmed giant cell arteritis in comparison to samples without giant cell arteritis.

Background (including reference to relevant literature) / rationale: An extensive search of the published literature (to date 7 August 2017 Embase and PubMed via Ovid, MedNar, and Cochrane) has identified inconsistent support for the role of varicella zoster virus in giant cell arteritis; (22). This intended project seeks to add to the global data for varicella zoster virus in giant cell arteritis to improve the power of statistical calculations.

Varicella zoster virus (also known as human herpesvirus 3) is a neurotropic alpha herpesvirus (17) that infects exclusively humans (1) and great apes, with no known animal reservoir (3); despite attempts an adequate animal model of the disease has not been established (23). The link between primary infection with varicella zoster virus in childhood causing chickenpox, and subsequent reactivation of the virus as herpes zoster (shingles) has been known for several decades (1, 10, 21, 24-26). Primary infection with varicella zoster virus of adults, pregnant females and immunocompromised people often results in a more serious disease state; with increased frequency of complications (4, 8, 26, 27). After primary infection with the varicella zoster virus does not clear the body, the virus lays dormant within the dorsal root ganglia (17, 26) of the nervous system and reactivates later in life when physiological, psychological, or emotional stresses reduce the body’s acquired immunity to the virus (28), typically several decades later (5, 28, 29).

Short and medium term complications of primary varicella infection include secondary staphylococcal or streptococcal infections of cutaneous lesions (vesicles) (30, 31), pneumonia and potential for encephalitis (20, 26, 31, 32). Vascular complications include intracranial haemorrhage and ischemic stroke (31, 33-37) in patients with primary infection; however these are exceedingly rare, occurring in less than 1 in 15,000 cases of chickenpox (31, 36).

Diagnosis of the typical uncomplicated primary varicella zoster virus infection (chickenpox) is based on clinical examination; findings include mild constitutional symptoms followed by the appearance of a characteristic itchy rash (28, 31, 38). The diagnosis can be confirmed with polymerase chain reaction (PCR) sequencing of serum from a skin lesion (39). Treatment of uncomplicated chickenpox in children is usually symptomatic (28, 31), simple analgesia and topical antipruritics as the disease is self limiting (28); whilst immunocompromised patients, pregnant females, neonates, adolescents and adults may require antiviral treatment or immunoglobulin therapy due to the increased severity of the infection and potential complications (28).

Prior to the introduction of a varicella vaccine primary infection with varicella zoster (chickenpox) was ubiquitous in childhood (28, 40), however with the inclusion of the vaccine on the national immunisation schedule for 18 month olds there has been a significant decline (41) in the number of cases of community-acquired chickenpox, and as a result the potential sequelae (2, 31, 34), with vaccination programmes morbidity and mortality associated with primary varicella virus infection have decreased by more than 95% (28, 31).

Reactivation of the dormant virus within the dorsal root ganglia results in herpes zoster (1).  Diagnosis of herpes zoster (shingles) can be either by laboratory methods (PCR as for chickenpox) (25, 28, 31) or by clinical examination; with the characteristic pain with or without rash in a dermatomal distribution that does not cross the patient’s midline. Complications occur when the dermatomal distribution is over the trigeminal nerve branches, particularly the ophthalmic branch (a specific diagnosis of herpes zoster ophthalmicus (HZO) is made)(42); this may result in keratitis, uveitis, and potentially vision loss; the incidence of direct ocular involvement in HZO has been as being as high as 50 – 72% (42). Treatment of the reactivation of zoster as shingles requires antivirals and pain management (43); and may be complicated with post herpetic neuralgia lasting several month after the cutaneous lesions have resolved (44, 45).

Giant cell arteritis is a vasculitis that typically affects patients in their 7th decade of life; it manifests variably with scalp tenderness, jaw pain, headache, and a spectrum of visual disturbances. Giant cell arteritis has an incidence between 7.2 and 33.6 new cases per 100,000 people over the age of 50 years (15, 16) predominantly in females of Caucasian European ancestry (16). It is an inflammatory condition of the vasculature, specifically it is a proliferation of giant nucleated cells within the vessel walls (12), predominantly the branches of the thoracic aorta, large arteries of the neck, and the branches of the external carotid artery (particularly the temporal, ophthalmic, and posterior ciliary arteries)(12, 14); this inflammation results in vessel occlusion and diminished blood flow; and ultimately ischemia to downstream tissues. The predominance of giant cell arteritis to affect extracranial blood vessels contrasts the short and medium term vascular complications of primary infection with varicella which dominantly affect the intracranial vessels resulting in intracranial haemorrhage (stroke).

The diagnosis of giant cell arteritis is fulfilment of the American College of Rheumatology (ACR) classification criteria as follows: “to be deemed as having GCA, patients must meet 3 of the following 5 criteria: (1) age over 50; (2) new-onset localized headache; (3) temporal artery tenderness or reduced pulse; (4) ESR of 50 mm/h or higher; (5) abnormal temporal artery biopsy findings demonstrating mononuclear infiltration or granulomatous inflammation” (46). The definitive diagnosis of temporal arteritis is histopathological confirmation of a temporal artery biopsy (16). Current treatment is with immunosuppressive doses of corticosteroids for extended duration to reduce the inflammation of the vasculature with or without a corticosteroid sparing agent (47).

The combined knowledge of varicella zoster virus causing vascular complications, the ability of the virus to lay dormant within the neural network, and the increasing incidence of giant cell arteritis with increasing age similar to the trend of herpes zoster, have led to the hypothesis that varicella zoster virus may contributing factor to giant cell arteritis (19, 20, 22, 48).

However there have also been a number of studies published that speculate that the relationship is only coincidental as varicella zoster is so ubiquitous (1, 17); these studies have either not identified the presence of varicella zoster in the temporal artery biopsy samples (49)  or showed no significant difference histopathologically between confirmed giant cell arteritis with and without the presence of varicella zoster virus (50).

The small sample numbers presented in the literature (15 for Kennedy et al (50), 64 for Mitchell and Font (49), 6 for Álvarez-Lafuente et al (51) 10 for Nordborg et al (19), 17 for Gilden and Nagel (52) 95 for Gilden and Nagel  (48) 103 for Cooper et al (53) and 30 for Helweg-Larsen (41)), limit the statistical power calculations, whilst the continued work of Gilden and colleagues at UC Denver support the hypothesis, Kennedy et al, Nordborg et al, and Álvarez-Lafuente all reject the hypothesis.

All published studies use the same methods as this proposal (that of histopathological confirmation of giant cell arteritis, and polymerase chain reaction for the determination of varicella zoster virus in tissue)  these methods provide excellent specificity and sensitivity. Determination of a statistical significance between the incidence of giant cell arteritis and varicella zoster within the samples analysed for this will be with a Chi-squared two sample comparison; with a P value of < 0.05 being statistically significant.

The implications of the intended research proposed in this study aim to determine the need to evaluate the current treatment of giant cell arteritis with an additional prospective cohort study. This potential trial would examine the efficacy of current treatment (corticosteroids) compared with corticosteroids plus a placebo and corticosteroids plus an antiviral; resulting in better patient management; more effective use of medications, targeted antiviral therapy, and a reduction in the potential complications; primarily vision loss (54). That is to say it would reduce morbidity associated with giant cell arteritis; improving patients’ quality of life.

With the inclusion of the live attenuated varicella vaccine on the national immunisation schedule it is probable if there is a causal link between varicella zoster and giant cell arteritis a decrease in incidence of giant cell arteritis would be observed over time; however as the latency between primary infection and virus reactivation is several decades this epidemiological results are pending. Recently  Lotan and Steiner (55) identified an increase in the incidence of giant cell arteritis following the introduction of varicella vaccination (41.6 per 100,000 in non-vaccinated, 75.2 per 100,000 in vaccinated population); however this result was obtained from epidemiological reports, it could be justified that the increase in incidence of giant cell arteritis was a result of the use of a live attenuated vaccine; the same mechanism by which the wild type virus remains dormant within the neural network of the host reflected by the Oka strain derived vaccine. That said, there has been no demonstrated increase in the incidence of herpes zoster corresponding to the introduction of the varicella vaccine (7).

Study aims / objectives: To objective of the intended research is to determine the presence of varicella zoster virus within temporal artery biopsy samples with histopathologically confirmed giant cell arteritis; and identify if there is a statistically significant increase in the presence of varicella zoster compared to samples without giant cell arteritis.

Hypothesis to be tested: Is there a statistically significant rate of detection of varicella zoster virus present within temporal artery biopsy samples with histopathologically confirmed giant cell arteritis compared to samples without giant cell arteritis.

Population / setting (anticipated number / ages / where / by whom): This study will use temporal artery biopsy samples that are currently stored in the Pathology West (formerly ICPMR) Tissue Bank, these samples have been collected for diagnosis of giant cell arteritis; they will be de-identified and have a non-coded identification number and the patients age and gender. There are currently 74 temporal artery biopsy samples held within the tissue bank. There are no inclusion criteria restrictions for the temporal artery biopsy samples to be used for this project. The histopathology and PCR will be undertaken by pathologists of the ICPMR, Westmead Hospital.

Intended Trial design / methods / power calculations / data analysis / statistical considerations: This project is a retrospective analysis of existing temporal artery biopsy samples maintained in an historical tissue bank; currently there are 74 individual samples available. The tissue samples will be analysed histopathologically to determine the presence or absence of giant cell arteritis, and with polymerase chain reaction gene amplification (PCR) to determine the presence or absence of varicella zoster virus. These two P/A data sets will provide the basis of a Chi-squared test for statistical significance with a P value of < 0.05 being statistically significant.

# Present # Absent Total
Varicella Zoster
Giant Cell Arteritis
Total 74

The power and statistical significance is governed by the samples size, and unfortunately the number of samples is limited, however as this is a pilot study it is anticipated it will provide enough strength for the basis of project expansion. Subsequent studies would aim to incorporate age matched control samples obtained from autopsy; however this would require additional ethics approval.

Intended Study procedures: Existing temporal artery biopsy samples (74 to date) have been identified for use in this project. These samples were obtained with patient consent during diagnostic work up of patients since the establishment of the Westmead Institute of Clinical Pathology and Medical Research (ICPMR); specific consent for these tissues to be used for further research may not explicitly have been obtained; however given the age of some of the samples re-identifying them and obtaining specific consent for this research would be not be feasible. It would not influence the patient management as this is only a pilot study.

The temporal artery biopsy samples are, de-identified, formalin-fixed, paraffin-embedded (FFPE) and are either histopathologically positive or negative for giant cell arteritis (GCA), they will be obtained from cryogenic storage within the Pathology West Tissue Bank (formerly ICPMR). As the samples are de-identified, and only the age and gender of the patient is known, all other clinical information pertaining to a medical history of chickenpox, herpes zoster (shingles), varicella or zoster vaccination, will not be available, thus not biasing results. Histology results will be documented for inclusion in statistical calculations. Following the methodology in the published literature, the current standard method for identification of varicella zoster virus within tissue samples is polymerase chain reaction gene amplification (PCR). To determine the presence of varicella zoster virus within the temporal artery biopsy sample (formalin fixed, paraffin-embedded) the varicella zoster DNA material must be extracted and amplified for detection; this is the method chosen globally for successfully extracting DNA from formalin fixed, paraffin embedded samples (56) this is done through extraction, denaturing, and amplification with polymerase chain reaction (56), and provides a sensitivity of greater than 85% for formalin fixed paraffin embedded tissue samples (56), using targeted primers specific for varicella zoster virus and enhanced amplification sensitivity and specificity of 100% and 99% respectively have been reported (57). Polymerase chain reaction is preferred to culture as it is more reliable at detection of varicella zoster virus (58-60) especially in formalin fixed, paraffin embedded tissue samples.

Briefly, the biopsy samples will then be sliced into 5μm sections, deparaffinised utilising xylene washes (1mL, 5 minutes, twice) the supernatant isolated and immersed in ethanol (1mL, twice) and the resulting supernatant removed through centrifugation (15,000 rpm, 2min) (53, 61) The resulting DNA material will then be extracted using Proteinase K lysis, specific to manufacturer’s instructions, cleaving the DNA to allow for priming with specific varicella zoster virus primer bases (62). The isolated varicella DNA material will then be amplified through multiple cycles of PCR to quantitate the varicella zoster (59, 63). The specific PCR methodology (temperatures, extraction times, solvent, diluent, concentrations and chemicals) will be determined by the manufacturer’s instructions of the instrumentation and sequencing kits utilised. Use of targeted primers to determine the strain of varicella is important to differentiate the potential for vaccination strains (Oka) being identified within the biopsy samples (59, 63, 64) The presence/absence of varicella zoster virus within the temporal artery biopsy samples will form the basis of 2-sample Chi Squared statistical analysis and p-value determination to assess correlation beyond coincidence of varicella zoster virus in giant cell arteritis; compared to biopsy negative samples.

Anticipated outcomes / measures / potential significance: The intended outcome of this pilot study is to determine if there is a statistical significance between the histopathologically confirmed presence of giant cell arteritis and the PCR confirmed varicella zoster virus within the same tissue samples.A safe and effective live attenuated varicella vaccine to provide vaccination against primary infection with varicella was introduced in Australia in 2005 (65) and a more potent herpes zoster vaccine (5) against shingles was introduced in 2016, however the latter only reduces incidence of shingles by 51% and post herpetic neuralgia by 66.5% (44). If there is statistical significance in the identification of varicella within the temporal artery biopsy samples these vaccines may help reduce the incidence of giant cell arteritis in the long term, and the associated sequelae of vision impairment or blindness. The latency of the varicella zoster virus means that several decades must elapse before accurate epidemiological data is available to determine the efficacy of the vaccine and its potential role in giant cell arteritis. The results of this study may also lead to future studies using additional tissue samples from other sites, and potential trials examining the efficacy of anti-viral agents in combination with corticosteroids for the treatment of giant cell arteritis.

Data security/storage & disposal: In accordance with the National Health and Medical Research Council’s Australian Code for the Responsible Conduct of Research all laboratory data will only be held on secure password encrypted PathWest computers.  Data will be stored for the duration of the project, and for 5 years after in accordance with the aforementioned NHMRC Code (§2.1.1).

Specimen disposal: At the completion of the laboratory investigations all specimens will be disposed of in appropriate biological hazard waste bins in accordance with local policy and procedure.

Anticipated start / finish dates: Intended commencement upon ethics approval by Western Sydney Local Health District Human Research Ethics Committee, completion 6 months after commencement.

Intended Monitoring / reporting: The project will adhere to the governance guidelines for human research ethics; specific to Western Sydney Local Health District and the National Health and Medical Research Council Statement on Ethical Conduct in Human Research (2007, update 2015). The results of this study will be disseminated though presentation at scientific meetings and by publication in the peer-reviewed literature.

Statement of ethical issues: This project is classified as a negligible risk; no new samples are being collected from patients, the samples have already been collected prior for the diagnosis of suspected giant cell arteritis. The samples have been obtained under the terms of routine surgical consent in the course of patients’ treatment and stored in the Westmead Tissue Bank since the opening of the hospital in 1979. Specific consent for the future use of retained tissue in medical research may not have been gained at the time of collection; practically this cannot be determined. Though re-identification is theoretically possible, many of the “participants” are deceased and re-identification is impractical and in many cases impossible and would place unnecessary burden on the researcher. There are no therapeutic implications for the participants as their treatment was undertaken according to the historical standard of care; re-identification would not  lead to a change of treatment at this late stage that would be likely to be of a clinically meaningful benefit. In accordance with the National Statement on Ethical Conduct in Human Research (2007, update 2015); a waiver for consent can only be granted by an  HREC for the use of stored tissue samples for this research project satisfying §2.3.10 and §2.3.11 of the National Statement.

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