Adenovirus and human papillomavirus in the pathogenesis of pterygium
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Summer 2021 • Vol 16 | No 1 Or iginal s tud y
SA Ophthalmology Journal Potential viral pathogenesis of pterygium 27
Adenovirus and human papillomavirus
in the pathogenesis of pterygium
EB van der Merwe MBChB(UP), PGDip Dentistry(Oral surgery), MMed(Ophth), FCOphth(SA); Stellenbosch University, Department of Surgical
Sciences, Division of Ophthalmology, Cape Town, South Africa
ORCID: https://orcid.org/ 0000-0003-0238-7782
J Maritz MBChB, MSc(Med), MMed(Virol Path), FC Path(SA)Viro; Stellenbosch University, Division of Medical Virology, Cape Town, South
Africa; PathCare Reference Laboratory, Cape Town, South Africa
ORCID: https://orcid.org/0000-0001-5311-9134
KE Delaney BSc(Molecular Biology and Biotechnology), BSc(Hons)(Medical Virology); Stellenbosch University, Division of Medical Virology,
Cape Town, South Africa
ORCID: https://orcid.org/0000-0001-5845-5778
D Smit MBChB, MMed(Ophth), FCOphth(SA), PhD; Stellenbosch University, Department of Surgical Sciences, Division of Ophthalmology,
Cape Town, South Africa
ORCID: https://orcid.org/0000-0003-3206-8184
Corresponding author: Dr Ernst Baard van der Merwe, Division of Ophthalmology, Room 5053, Faculty of Medicine and Health Sciences,
Stellenbosch University, Francie van Zijl Drive, Parow Valley, 7500, South Africa; tel: +264 81 5503993; email: v_ernst_baard@hotmail.com
Abstract
Background: Current understanding of the pathogenesis of one (11.1%) tested positive for HPV and none tested positive
pterygium is incomplete. One theory proposes a multi-step for AdV.
model for the pathogenesis of pterygium and suggests that Conclusion: The HPV prevalence of this study is in accordance
ocular surface viral infections might play an important role. with other similar studies from elsewhere although AdV
Human papillomavirus (HPV) has been identified as a co-factor prevalence is significantly lower than the one other similar
in susceptible hosts, and adenovirus (AdV) has also been study. The significance of the average age differences and the
implicated as a causative organism. This paper describes the link with HIV requires further investigation.
frequency with which these two viruses were isolated from
excised pterygia in a Namibian population. Keywords: adenovirus, human papillomavirus, Namibia,
Methods: In this cross-sectional descriptive study, the pterygium, virus, viral pathogenesis
primary objective was to determine the prevalence of HPV and
AdV isolated from pterygium samples of patients in a Namibian Funding: Stellenbosch University, Division of Ophthalmology,
population. Viral nucleic acid extraction and polymerase chain Departmental research fund – EB van der Merwe
reaction (PCR) were performed on 66 tissue samples from Poliomyelitis Research Foundation Bsc (Hons) bursary –
66 patients. J Maritz and KE Delaney
Results: Of the 66 samples, 21 (31.8%) had a positive PCR National Research Foundation Honours Innovation bursary –
result of which 15 (22.7%) were HPV positive and six (9.1%) were J Maritz and KE Delaney
AdV positive. The mean age of HPV-positive patients was more Postgraduate merit bursary from Stellenbosch University –
than eight years lower than that of HPV-negative patients, and EB van der Merwe and KE Delaney
the mean age for the AdV-patients was more than seven years
higher than that of AdV-negative patients. Of the nine human Conflict of interest: None of the authors have any conflicts of
immunodeficiency virus (HIV)-positive patients included, only interest to declare with respect to this study.Or iginal s tud y Vol 16 | No 1 • Summer 2021 28 Potential viral pathogenesis of pterygium SA Ophthalmology Journal Introduction 2012, a total of 18 and 16 studies looked Ophthalmology at Windhoek Central A pterygium is a wing-shaped ocular at the prevalence of HPV in pterygia and Hospital to conduct the research there. surface ingrowth of bulbar conjunctiva OSSN respectively, and the results were The research followed the tenets over the limbus onto the cornea.1 It 18.6% for pterygium and 33.8% for OSSN. of the Declaration of Helsinki and may compromise vision either by direct Even though the range in prevalence of informed consent was obtained from all obstruction of the visual axis or by 0–100% for both conditions suggested participants after the nature and possible causing significant astigmatism.1-3 The possible study design differences and consequences of the study were explained limbal tissue was identified in 1983 by virus identification technique problems, to them, making use of an interpreter Cameron as the site of pathogenesis.4 it was still concluded that HPV may be a if required. Most textbooks classify a pterygium as co-factor in susceptible hosts. 24 a degenerative lesion.1,2 Recently it has The other issue arising in most studies Collection also been described as a proliferative is the lack of evidence regarding the All participants were patients booked for lesion resembling an aberrant wound- mechanism of HPV infection of the ocular surgical removal of pterygia at Windhoek healing process with typical histological surface.7,24 One virus with well-established Central Hospital’s Eye Clinic. This clinic features. 5,6 Mild inflammatory changes ocular involvement is adenovirus (AdV). usually does an average of 20 pterygium are frequently present 2 and of note is Viral infection is the cause in up to 80% excisions per week and includes patients evidence of a reactive fibrovascular of cases of acute conjunctivitis, and from all regions in Namibia. Patients are stroma with epithelial–mesenchymal AdV is the identified virus in 65–90% seen by ophthalmic assistants at eye transition and neovascularisation, of cases of viral conjunctivitis.1,25 clinics all over the country and booked published by Chui in 2011.6 Clinical presentation varies from for surgery at Windhoek Central Hospital’s Most authors agree that the mild subclinical disease to severe Eye Clinic. Patients included in this study pathogenesis of pterygium remains inflammation with significant morbidity were patients presenting for surgery an ophthalmic enigma.6,7 Recent and affects immunocompetent as well as booked on these routine lists. Only research has focused on anti-apoptotic as immunocompromised patients.1,25-27 patients older than 18 years of age with mechanisms, immunological mechanisms, Of interest are studies examining the a clinical diagnosis of pterygium made cytokines, growth factors, extracellular effect of adenovirus E1A protein on by the first authoron the day of surgery matrix modulators, genetic factors and p53. 28-30 Another study examined the were included. We appreciate that there viral infections as causative factors. 8 persistence of adenovirus in the tear is poor correlation between clinical The prevalence of pterygium differs film and found evidence of adenovirus examination and histological results. The significantly according to geographic DNA in the tear films of patients up to decision to consider a lesion as benign location.9-11 Ultraviolet radiation exposure a decade after first presentation with pterygium is based on the absence of and other environmental factors including conjunctivitis, thus suggesting the ability features that would be considered atypical hot, dry and windy conditions and of the virus to persist in the conjunctiva or suspicious. Suspicious features include chronic dust exposure are considered or lacrimal apparatus. 31,32 However, in the short mean duration since first noticing to contribute significantly to the literature there is only one study that the lesion, fast and aggressive growth, pathogenesis but there is little conclusive looked at the role of AdV in ophthalmic lesion not situated at the interpalpebral evidence to support this.12-15 Inheritance pterygium ormation. 33 limbus, presence of an obvious feeder was suggested to play a role as early Namibia is a country in south-western vessel, presence of inflammation, as 196016 but evidence only suggests a Africa. The population according to the presence of leukoplakia or pigmented contributory role in some cases.17 last census in 2011 is just over 2.1 million. 34 lesions, nodular or papilliform surface or All of the above lead to the suggestion The Namibian climate is largely arid to irregular border. 35 of a multi-step model (also called a two- semi-arid with high levels of UV exposure All patients were examined by the first hit model) concept for the pathogenesis which sets the scene for a high incidence author pre-operatively and the presence of pterygium,7 with the suggestion that and prevalence of both pterygium and of any atypical or suspicious features ocular surface viral infections might OSSN although these have not yet been as well as refusal to participate in the play an important role.7 The idea is formally reported. study resulted in exclusion from the supported by the discovery of abnormal study. The first author completed a case expression of the p53 tumour suppressor Methods report form (Figure 1) for all participants gene in pterygium samples.18-20 Due to The primary objective of the study was and completed the questions on this the well-known and established link to determine the prevalence of HPV and form himself. Questions included for the between human papillomavirus (HPV) AdV isolated from pterygium samples secondary objective were the age of the and cervical cancer due to p53 and HPV obtained from patients from all regions patients, the sex of the patients, presence protein E6 and E7 association, 21,22 this in Namibia. The secondary objective was of unilateral or bilateral pterygium (for was the first virus to be implicated and to look at other contributing factors that patients with bilateral pterygia only one thus researched as a possible co-factor could be associated with the formation eye was operated), history of previous for the pathogenesis of pterygium. With of pterygia. The study was designed eye infections, other eye problems or this suggested oncogenic origin and the as a cross-sectional descriptive study. treatment, smoking status, main source idea of pterygium as a premalignant Ethics approval was obtained by the of cooking (open fire, gas or electricity) lesion,6,23 numerous studies looked at the Health Research Ethics Committee of and working conditions (mainly indoors or prevalence of HPV in pterygia and ocular Stellenbosch University, Cape Town, mainly outside). surface squamous neoplasia (OSSN). In South Africa (S16/12/242), and permission Informed consent for the surgery as a review published by Di Girolamo in was obtained from the Department of well as informed consent for inclusion
Summer 2021 • Vol 16 | No 1 Or iginal s tud y
SA Ophthalmology Journal Potential viral pathogenesis of pterygium 29
in the study was obtained from every to the Division of Medical Virology at the protocol for DNA purification from
patient. All pterygium excisions were Faculty of Medicine and Health Sciences tissues was followed and complete tissue
performed by the same first author and of Stellenbosch University in Cape Town, lysis was achieved in three hours. The
66 specimens were collected from 66 eyes South Africa, for further testing. extracted nucleic acid was quantified and
of 66 patients. Histological examination assessed using a NanoDrop® ND-1000
of clinically unsuspicious samples was not PCR testing Spectrophotometer (Thermo Scientific,
performed due to financial constraints. Nucleic acid extraction Waltham, Massachusetts), and the eluate
The tissue for viral testing was labelled Viral nucleic acid was extracted from was stored at −20 °C.
and stored in a refrigerator in a 2 ml pterygium samples using a commercially
Eppendorf tube filled with normal saline. available QIAamp® DNA Mini Kit (Qiagen, Polymerase chain reaction (PCR)
The samples were then couriered en bloc Hilden, Germany). The manufacturer’s All extracted samples were subjected to
three PCRs using a commercial GeneAmp®
Patient name____________________________________Age______ Male/Female_____ Study nr _____________ PCR System 9700 (Applied Biosystems,
Foster City, California). All PCR reactions
Ethnicity included appropriate positive and
Ovambo Kavango Coloured Herero Damara negative controls.
A human beta-globin gene PCR served
White Nama Lozi San Tswana
as an internal control for each sample.
Other Amplification of each sample was achieved
using 10 µl of DNA eluate together with
Region GoTaq® G2 Flexi DNA Polymerase kit
Zambezi Erongo Hardap II Karas Kavango Kavango Khomas (Promega, Madison, Wisconsin) at the
east west recommended concentration, 1 µl of PCR
nucleotide mix (10 mM of each dNTP),
Kunene Ohangwena Omaheke Omusati Oshana Oshikoto Otjizondjupa
0.5 µl of 5 u/µl GoTaq® G2 Flexi DNA
Polymerase and 5 µM of primers GH20 and
Pterygium
PC04 in a total volume of 50 µl. 36 Forty
Laterality Unilateral Bilateral cycles of amplification were performed
Side Right Left that consisted of an initial denaturation
Orientation Nasal Temporal step at 95 °C for 10 minutes followed by
cycling through 95 °C for 30 seconds, 55 °C
Primary or recurrent Primary Recurrent
for 30 seconds (annealing step) and 72 °C
History of previous pink eyes?________________________________________________________________________ for 30 seconds (elongation step).
HPV PCR was performed using the
Other previous eye diagnosis?________________________________________________________________________
widely accepted consensus primers, MY09
Previous eye surgery?___________________________________________________________________________________ and MY11. 37 These primers targeted a 450
bp fragment of the HPV genome. PCR was
Other current eye problems?__________________________________________________________________________
performed using the same concentrations,
volumes and PCR conditions as described
HIV status
above but with 50 µM of each primer, in a
Positive Negative Unknown total volume of 50 µl.
If positive: CD4 count ___________________________________________________________________________________ Human adenovirus PCR targeted a
conserved hexon gene. Primer set AVF
Smoking and AVR 38 was utilised and successful
amplification yielded a 300 bp product.
Yes No
A 50 µl PCR was performed containing
10 µl of DNA template, each primer at a
Source of cooking concentration of 10 µM, 2.5 µl of 25 mM
Fire Gas Electricity MgCl2 was used and the remaining
reagents from the GoTaq® G2 Flexi DNA
Working conditions Polymerase kit were used at the supplied
concentrations and recommended
Mainly outdoors Mainly indoors
volumes (Promega, Madison, Wisconsin).
The AdV PCR programme consisted of
PCR results an initial denaturation step at 95 °C for
HPV four minutes, followed by 40 cycles, each
Positive Negative consisting of cycling through 95 °C for 30
seconds, 59 °C for 30 seconds and 72 °C
Adenovirus for 30 seconds.
PCR products from all three reactions
Positive Negative
were stored at 4 °C prior to gel
Figure 1. Case report form electrophoresis. Products were run inOr iginal s tud y Vol 16 | No 1 • Summer 2021
30 Potential viral pathogenesis of pterygium SA Ophthalmology Journal
Table I: Demographic data – HPV a 1.5% agarose gel submerged in 1X SB
buffer and visualised by exposure to
Characteristics Total HPV-positive HPV-negative p-value
ultraviolet-light using an UVIprochemi II
Age in years – mean (SD) 46.97 (13.893) 40.73 (10.299) 48.80 (14.357) 0.047
D-77LS-26M (Uvitec, Cambridge, United
Sex – n (%) Kingdom). Five microlitres of each PCR
Male 27 (40.9) 8 (29.6) 19 (67.8) 0.207 product were mixed with 1 µl of Novel
Female 39 (59.1) 7 (17.9) 32 (82.1) Juice (GeneDirex, Taiwan, China) and
loaded into an agarose gel well, together
Ethnicity – n (%)
with 5 µl of Promega’s 1 kb DNA Ladder
Mixed 8 (12.1) 2 (25) 6 (75) 0.587
(Promega, Madison, California) loaded
Black African 58 (87.9) 13 (22.4) 45 (77.6) into the first well of each gel to serve as
Laterality – n (%) a reference for determining amplicon size.
Unilateral 20 (30.3) 5 (25) 15 (75) 0.502 PCR products were then stored at −20 °C.
Bilateral 46 (69.7) 10 (21.7) 36 (78.3)
Data and analysis
Working conditions – n (%)
All the results of the PCR tests and
Indoors 35 (53.0) 8 (22.8) 27 (77.1) 0.606 questionnaires were entered into an Excel
Outdoors 31 (47.0) 7 (22.6) 24 (77.4) spreadsheet and data was analysed and
Smoking – n (%) interpreted with SPSS software (version
25) with guidance and assistance from
Yes 12 (18.2) 3 (25) 9 (75) 0.550
the Biostatistics Unit at Stellenbosch
No 54 (81.8) 12 (22.2) 42 (77.8)
University’s Faculty of Medicine and Health
Sciences. Student t-tests were used for
Table II: Demographic data – AdV average age calculations while chi-square
tests as well as Fisher’s exact test were
Characteristics Total AdV-positive AdV-negative p-value
done on all other parameters. For the
Age in years – mean (SD) 46.97 (13.893) 53.67 (15.603) 46.30 (13.675) 0.218 results, the Fisher’s exact test results
Sex – n (%) were used.
Male 27 (40.9) 2 (7.4) 25 (92.6) 0.525
Female 39 (59.1) 4 (10.3) 35 (89.7) Results
Of the 66 samples from the 66 patients,
Ethnicity – n (%)
21 (31.8%) had a positive PCR test for one
Mixed 8 (12.1) 1 (12.5) 7 (87.5) 0.555 of the two viruses. Fifteen (22.7%) tested
Black African 58 (87.9) 5 (8.6) 53 (91.4) positive for HPV, and six (9.1%) tested
Laterality – n (%) positive for adenovirus. No sample tested
Unilateral 20 (30.3) 2 (10) 18 (90) 0.595 positive for both viruses.
Tables I and II show demographic data
Bilateral 46 (69.7) 4 (8.7) 42 (91.3)
and the relationship to HPV and AdV
Working conditions – n (%) status respectively.
Indoors 35 (53.0) 4 (11.4) 31 (88.6) 0.397 The mean age of the study population
Outdoors 31 (47.0) 2 (6.5) 29 (93.5) was 46.97±13.89 years. For the HPV-positive
Smoking – n (%) patients, the mean age was more than
eight years lower than the mean age of
Yes 12 (18.2) 2 (16.7) 10 (83.3) 0.298
the HPV-negative patients (p=0.047). For
No 54 (81.8) 4 (7.4) 50 (92.6) the AdV-positive patients, the mean age
was more than seven years higher than
Table III: HIV association in HPV and AdV the AdV-negative group.
More males (29.6%) than females (17.9%)
HIV association in HPV
tested positive for HPV, while more
Total HPV-positive HPV-negative p-value females (10.3%) than males (7.4%) tested
HIV – n (%) positive for AdV.
Positive 9 (13.6) 1 (11.1) 8 (88.9) 0.286 Of the 66 patients included, 30.3% had
Negative 40 (60.6) 11 (27.5) 29 (72.5) unilateral disease and 69.7% had bilateral
disease (samples were only collected from
Unknown 17 (25.8) 3 (17.6) 14 (82.4)
one eye per patient).
HIV association in AdV Outdoor working conditions (p-values
Total AdV-positive AdV-negative p-value 0.979 and 0.397), cooking mainly with open
HIV – n (%) fires and smoking (p-values 0.835 and
Positive 9 (13.6) 0 (0) 9 (100) 0.345 0.298) did not show any relationship with
either HPV or AdV status.
Negative 40 (60.6) 5 (12.5) 35 (87.5)
The HIV status of the patients was also
Unknown 17 (25.8) 1 (5.9) 16 (94.1) considered (Table III). Seventeen of theSummer 2021 • Vol 16 | No 1 Or iginal s tud y
SA Ophthalmology Journal Potential viral pathogenesis of pterygium 31
patients had unknown HIV status and Regarding laterality, the idea was to locations or by reviewing data from
refused voluntary testing after appropriate see if HPV-positive and AdV-positive previous studies.
counselling. Of the 49 patients whose results were more prevalent in samples The link between HIV with HPV and AdV
status was known, nine (18.4%) were HIV from patients with unilateral or bilateral in pterygia warrants further investigation
positive. Of the nine HIV-positive patients, disease. No statistical significance was and more research is needed to determine
only one (11.1%) tested positive for HPV, found. A study where samples from whether there are other possible links
and there were 11 HPV-positive patients both eyes are tested in patients with between virus-associated pterygia and the
with a known HIV-negative status. No HIV- bilateral disease will help explore this formation of OSSN.
positive patient tested positive for AdV, hypothesis further.
and five patients who tested positive for Only four patients had a recurrent Acknowledgements
AdV had a known HIV-negative status. pterygium and of these only one (25%) The Ministry of Health and Social Services
tested HPV positive. Therefore, we do of the Republic of Namibia.
Discussion not have sufficient data to comment on The staff of the Ophthalmology
The incidence of pterygium samples whether a correlation might exist between Department at Windhoek Central Hospital,
that tested HPV positive in our study recurrence and presence of HPV or AdV. especially Sr E Mbandeka, Dr H Ndume and
population (22.7%) is in accordance with Whether working environment was Dr S Obholzer.
the 18.6% published by Di Girolamo in mainly indoors versus outdoors did Pathcare Laboratories in Windhoek,
2012. 24 The incidence of AdV in our study not reveal any significant relationship Namibia and at N1 City, Cape Town for the
(9.1%) is significantly lower than the between HPV-positive and HPV-negative transport of the samples.
100% in the one other published study. 33 as well as AdV-positive or AdV-negative Mr M McCaul, researcher at Biostatistics
This confirms the accepted correlation samples. Smoking status also did not Unit, Centre for Evidence-based Health
between HPV and pterygium but questions reveal any statistical significance. Care, Department of Global Health,
the proposed correlation of AdV and We set out to determine whether Faculty of Medicine and Health Sciences,
pterygium formation. there may be a correlation between HIV Stellenbosch University, for his help and
An interesting finding is the lower infection and testing positive for HPV guidance with the data analysis.
average age of HPV-positive cases and/or AdV. Of the patients in our study
compared to HPV-negative cases as well with a known HIV status, 18.1% were References
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