The prevalence of human papillomavirus in ocular surface squamous neoplasia in HIV positive and negative patients in a South African population.

PURPOSE: To assess the prevalence and subtypes of Human Papillomavirus (HPV) in Ocular Surface Squamous Neoplasia (OSSN) in Human Immunodeficiency Virus (HIV) positive and negative patients in South Africa. BASIC PROCEDURES: This study was a single center retrospective cross-sectional study, conducted at Tygerberg Hospital, Western Cape, South Africa. We assessed 63 histopathologically confirmed OSSN formalin-fixed paraffin-embedded (FFPE) tissue blocks from 2015-2023. The presence of HPV was determined using the Hybrispot Direct Flow Chip Kit. Corresponding clinical data was retrieved from the National Health Laboratory Service (NHLS) central data warehouse. MAIN FINDINGS: Of the confirmed OSSN samples, 66.7% tested positive for HPV (95% confidence interval [CI] 54-77.3%). Of the 42 HPV positive samples, 38 (90.5%) had one or more known genotypes detected and 4 had unknown genotypes. The most prevalent subtypes were HPV 11, 16 and 18 (found in 61.9%, 52.4% and 33.3% of HPV positive samples respectively). 88.9% of the lesions biopsied were from HIV positive patients, of whom 56.4% had a CD4 + count of < 200 cells/µL. A lower median CD4 + count was detected among HIV positive patients with invasive squamous cell carcinoma compared to those with moderate dysplasia (p < 0.0198). CONCLUSIONS: There is a high prevalence of HPV in OSSN in South Africa. Certain subtypes namely, 11, 16, 18, 31, 33 and 35 may be more carcinogenic. HIV with HPV co-infection may be linked as a causative factor in the development of OSSN.

Host urinary biomarkers in HIV positive and HIV negative patients with tubercular uveitis and other uveitic diseases.

PURPOSE: To determine if host urinary biomarker profiles could distinguish between tubercular uveitis (TBU) and other uveitic diseases (OUD) in patients with and without HIV infection. METHODS: Concentrations of 29 different host biomarkers were measured in urine samples using the Luminex platform. Data were analyzed to describe differences between patients diagnosed with and without TBU and with and without HIV co-infection. RESULTS: One-hundred-and-eighteen urine samples were collected and 39% participants were diagnosed as TBU+. Mean age TBU+ was 39.3±13.6 years with 45.7% males. Anterior and panuveitis and unilateral involvement were most common. 32.6% were TBU+HIV+ (median CD4+=215) while 40.2% were OUD+HIV+ (median CD4+=234). Only sVEGF3 was decreased in TBU+ versus OUD+ (p=0.03), regardless of HIV status. Some biomarkers were significantly raised in HIV+ TBU+ compared to HIV- TBU+: sIL-6Rα, CD30, sRAGE , sTNFR I&-II, IP-10, MIP-1ß, sEGFR and Ferritin. HIV+ OUD+ had increased sVEGFR3, CD30, sIL-6Rα, IP-10, sTNFR I&-II, Ferritin and Haptoglobin compared to HIV- OUD+. VEGF-A (p = 0.04) was decreased in HIV+ OUD+ versus HIV- OUD+. CONCLUSION: Decreased urinary concentrations of VEGFR3 were observed in TBU+ compared to TBU-. HIV+ individuals demonstrated increased concentrations of multiple urinary analytes when compared to HIV- patients with uveitis.

Systemic and Ocular Manifestations of Arboviral Infections: A Review.

PURPOSE: To provide an overview of pre-selected emerging arboviruses (arthropod-borne viruses) that cause ocular inflammation in humans. METHODS: A comprehensive review of the literature published between 1997 and 2023 was conducted in PubMed database. We describe current insights into epidemiology, systemic and ocular manifestations, diagnosis, treatment, and prognosis of arboviral diseases including West Nile fever, Dengue fever, Chikungunya, Rift Valley fever, Zika, and Yellow fever. RESULTS: Arboviruses refer to a group of ribonucleic acid viruses transmitted to humans by the bite of hematophagous arthropods, mainly mosquitoes. They mostly circulate in tropical and subtropical zones and pose important public health challenges worldwide because of rising incidence, expanding geographic range, and occurrence of prominent outbreaks as a result of climate change, travel, and globalization. The clinical signs associated with infection from these arboviruses are often inapparent, mild, or non-specific, but they may include serious, potentially disabling or life-threatening complications. A wide spectrum of ophthalmic manifestations has been described including conjunctival involvement, anterior uveitis, intermediate uveitis, various forms of posterior uveitis, maculopathy, optic neuropathy, and other neuro-ophthalmic manifestations. Diagnosis of arboviral diseases is confirmed with either real time polymerase chain reaction or serology. Management involves supportive care as there are currently no specific antiviral drug options. Corticosteroids are often used for the treatment of associated ocular inflammation. Most patients have a good visual prognosis, but there may be permanent visual impairment due to ocular structural complications in some. Community-based integrated mosquito management programs and personal protection measures against mosquito bites are the best ways to prevent human infection and disease. CONCLUSION: Emerging arboviral diseases should be considered in the differential diagnosis of ocular inflammatory conditions in patients living in or returning from endemic regions. Early clinical consideration followed by confirmatory testing can limit or prevent unnecessary treatments for non-arboviral causes of ocular inflammation. Prevention of these infections is crucial.

Southern African HIV Clinicians Society Guideline for the clinical management of syphilis.

Syphilis, 'the great imitator', caused by Treponema pallidum infection, remains a complex and multifaceted disease with a rich history of clinical diversity. This guideline aims to be a comprehensive guide for healthcare workers in Southern Africa, offering practical insights into the epidemiology, pathogenesis, clinical manifestations, diagnostic testing, therapeutic principles, and public health responses to syphilis. Although the syphilis burden has declined over the years, recent data indicate a troubling resurgence, particularly among pregnant women and neonates. This guideline highlights the diagnostic challenges posed by syphilis, stemming from the absence of a single high-sensitivity and -specificity test. While treatment with penicillin remains the cornerstone of treatment, alternative regimens may be used for specific scenarios. We highlight the importance of thorough patient follow-up and management of sex partners to ensure optimal care of syphilis cases. In the context of public health, we emphasise the need for concerted efforts to combat the increasing burden of syphilis, especially within high-risk populations, including people living with HIV.

Differences in biomarker concentrations in serum and urine of patients with Ocular Tuberculosis - A prospective descriptive study.

PURPOSE: To describe biomarker concentrations in serum and urine of South African patients with ocular tuberculosis (OTB). METHODS: A prospective study to compare 29 urine and serum biomarkers in 14 OTB patients at a tertiary eye clinic. RESULTS: Median age of participants (7 male and 7 female) was 38.5 years (range 25-73) Most biomarker concentrations were significantly higher in serum than in urine (p < 0.01). Only 2 (IL-1RA and IL-2) showed higher concentrations in urine than serum (p < 0.01). Three biomarkers (sIL-2Ra, sTNFRI and IFNγ) showed no difference in concentration between urine and serum (p > 0.05). CONCLUSIONS: Most biomarkers tested showed significant differences in concentration between serum and urine and therefore these 2 biofluids cannot be used interchangeably when studying biomarker profiles. One notable exception is IFNγ as its concentration did not differ between serum and urine.

A Review of Human Ocular RNA Virus Infections Excluding Coronavirus, Human T-Cell Lymphotropic Virus, and Arboviruses.

We provide an updated review of pre-selected RNA viruses causing ocular inflammation in humans. RNA viruses such as coronaviruses and arboviruses are reviewed elsewhere. A Google Scholar search was conducted to identify recent publications on ocular inflammation caused by the RNA viruses specified here. Human RNA viruses target a wide range of ocular tissues from the anterior to the posterior. Influenza, measles and mumps cause anterior segment manifestations including conjunctivitis and keratitis, while retinitis and optic neuritis may be seen posteriorly. Newcastle disease and RSV cause conjunctivitis, whereas HIV causes characteristic anterior uveitis. Cataracts, microphthalmos, and iris abnormalities are common in congenital Rubella, while Rubella virus is associated with Fuchs uveitis syndrome. Newer technologies make it possible to detect more than one pathogen if present simultaneously. RNA viruses may produce significant ocular morbidity, and care should be taken to investigate ocular symptoms during disease outbreaks.

CXCL13, CXCL10 and CXCL8 as Indicators of Ocular and Neurological Involvement in Patients With Ocular Syphilis: An Observational Descriptive Study.

Aim: To investigate the role of the chemokines CXCL13, CXCL10 and CXCL8 in the diagnosis of ocular- and neurosyphilis by examining the serum, aqueous humour (AH) and cerebrospinal fluid (CSF) of patients with ocular syphilis. Methods: An observational descriptive study was performed prospectively at Tygerberg Academic Hospital in Cape Town, South Africa from 1 February 2018 till 31 January 2021 which enrolled 23 participants. 14 Patients were male and 9 female, 15 patients were HIV positive, and all patients were newly diagnosed with ocular syphilis. Upon diagnosis of ocular syphilis, the HIV status of each patient was determined, and 3 samples (AH, serum and CSF) were collected to measure the levels of CXCL13, CXCL10 and CXCL8 in each. All patients were treated with 14 days of intravenous Penicillin G and topical corticosteroid drops for uveitis. Results: The mean concentrations of all 3 biomarkers were higher in the AH and CSF than in the serum. The mean concentrations of the 3 measured biomarkers were markedly different when comparing both AH and CSF levels to serum levels. The level of CXCL13 measured in the AH correlated well with the concentrations found in the CSF of patients with neurosyphilis. In patients with neurosyphilis, mean AH levels of CXCL13 and CXCL10 were markedly higher than in serum while mean CSF levels of CXCL10 were also markedly higher than in serum. Also, the AH/serum ratio of CXCL13 and CXCL10, as well as the CSF/serum ratio of CXCL10, was much higher in patients with neurosyphilis than without. In patients with HIV infection, mean AH CXCL13 levels were much higher than in patients without HIV infection. Conclusion: The levels of CXCL13, CXCL10 and CXCL8 in the AH of patients with neurosyphilis are similar to previously reported levels in the CSF of patients with neurosyphilis and can potentially be an adjunct in the diagnosis of ocular syphilis. Patients with ocular syphilis who tested negative for neurosyphilis with conventional CSF testing showed features of neurosyphilis when analysing the CSF chemokines.

Clinical and laboratory characteristics of ocular syphilis and neurosyphilis among individuals with and without HIV infection.

BACKGROUND/AIMS: In the era of increasing incidence of syphilis globally, ocular syphilis is re-emerging as an important cause of uveitis. The aim of this study was to determine the clinical and laboratory characteristics of ocular- and neurosyphilis among individuals with and without HIV infection. METHODS: Retrospective analysis of patients diagnosed with ocular syphilis presenting to Tygerberg Hospital, South Africa, over a 5-year period ending December 2018. RESULTS: Two-hundred and fifteen eyes of 146 patients were included. HIV coinfection was present in 52.1% of the patients, with 23.7% of these patients being newly diagnosed on presentation. The median age was 36.5±9.8 years. Bilateral involvement occurred in 47.3%, with 68.1% of these patients being HIV positive. The most frequent form of intraocular inflammation was posterior uveitis (40.9%), followed by panuveitis (38.1%), both of which were more predominant in HIV-positive eyes. Seventy-four per cent of all eyes had a visual acuity ≤20/50 and 40% <20/200 at presentation. A lumbar puncture was performed in 113 patients (77.4%). Sixteen patients had confirmed neurosyphilis and 27 probable neurosyphilis according to the UpToDate algorithms. CONCLUSION: This study included the largest number of ocular syphilis cases with the largest proportion of HIV infection to date. Forty-three of 146 patients (37.0%) had neurosyphilis. HIV status must be determined in all patients with ocular syphilis since almost » of patients were newly diagnosed with HIV infection by doing so.

Presumed tuberculous sclerokeratouveitis in immunocompetent South African patients.

BACKGROUND/OBJECTIVES: Ocular tuberculosis remains a diagnostic challenge since its clinical presentation is so variable. We describe the clinical characteristics of patients presenting with sclerokeratouveitis secondary to presumed Mycobacterium tuberculosis infection. METHOD: Retrospective analysis of 14 patients presenting with sclerokeratouveitis to Tygerberg Hospital. All patients underwent: (1) detailed ophthalmological evaluation, (2) tuberculin skin test (TST), (3) chest X-ray to assess for systemic disease, and (4) laboratory investigations to exclude other causes of ocular inflammation. Tuberculous sclerokeratouveitis was diagnosed if: (1) clinical findings showed scleritis with adjacent peripheral keratitis and anterior uveitis, (2) TST was positive, (3) other causes of sclerokeratouveitis were excluded, and (4) positive response to tuberculosis treatment without adjunctive anti-inflammatory agents was noted. RESULTS: Seventeen eyes were included. Mean age was 29.1 ± 12.1 years. All patients were females with no history of previous/current pulmonary tuberculosis. Only one patient was HIV positive, but virologically suppressed. All patients had a strongly positive TST result. Scleral involvement was nodular in four patients and diffuse in ten. Corneal involvement manifested as ill-defined peripheral stromal opacities adjacent to the area of scleritis with deep corneal stromal vessels. Corneal sensation was decreased in all involved eyes. All patients responded to tuberculosis treatment with complete resolution of the sclerokeratouveitis. CONCLUSIONS: In our highly endemic area, tuberculous sclerokeratouveitis is seen in young, immunocompetent patients, and responds well to tuberculosis treatment without concurrent immunosuppression. Decreased corneal sensation may lead to an incorrect diagnosis of herpetic infection if a high index of suspicion is not maintained for ocular tuberculosis.

Corneal Involvement in HIV-infected Individuals.

Corneal involvement in HIV-infected individuals may be broadly classified into two categories, namely, infectious and noninfectious with the vast majority of manifestations occurring in the former. In this article, we shall focus on these two categories and strive to highlight those presentations that should alert the clinician to suspect underlying HIV infection. Infectious group mainly consists of Herpitic group of viral infections. Bacterial causes may be due to Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeroginosa, alpha hemolytic Streptococcus, Micrococcus and Bacillus. Fungalf keratitis in HIV-infected individuals depends on the geographic locations from which patient comes. Microsporidia and Acanthamoeba are common Protozoal causes. Non-infective inflammatory causes include peripheral ulcerative keratitis, keratoconjunctivitis sicca, and squamous cell carcinoma of the conjunctiva. Severity which is abnormally severe or very minimally reactive makes the clinician suspect of immunosuppression.

Evaluation of Potential Antigen-specific Host Biomarkers in QuantiFERON Supernatants as Candidates for the Diagnosis of Ocular Tuberculosis.

Purpose: To evaluate potential host biomarkers detectable in QuantiFERON supernatants as diagnostic candidates for ocular tuberculosis (OTB).Methods: We investigated 47 host markers in QuantiFERON supernatants from 92 individuals with uveitis using the Luminex platform. We evaluated the potential of individual and combined biomarkers to distinguish between patients with possible, probable, and no OTB.Results: Differences were observed in median concentrations of several biomarkers including IL-13, IFN-γ, IFN-α2, and IL-1ß, in individuals with OTB versus no OTB regardless of HIV status. Individuals with probable and possible OTB only differed regarding GM-CSF. We identified a four-marker biosignature (CD40 L, IL-33, IFN-γ, and SAP) which diagnosed OTB with an area under the ROC curve of 0.80, sensitivity = 56.3% and specificity = 90.0%.Conclusion: This represents the first attempt at screening QuantiFERON supernatants for biomarkers to diagnose OTB. We identified candidate biosignatures which may aid in diagnosing OTB in both HIV positive and negative patients.

Identification of Potential Biomarkers in Peripheral Blood Supernatants of South African Patients with Syphilitic and Herpetic Uveitis.

Purpose: To identify potential diagnostic biomarkers for herpetic and syphilitic uveitis.Methods: Blood samples were collected from 92 uveitis patients. Concentrations of 47 biomarkers were evaluated in unstimulated Quantiferon supernatants using the Luminex platform.Results: Results showed 11 patients (12%) had herpetic uveitis, 11 (12%) syphilis, 40 (43.5%) other infectious causes, 16 (17.4%) established noninfectious causes and 14 (15.2%) were idiopathic. Biomarker analysis revealed three proteins (Apo-A1, Apo-CIII, CRP) that differed between syphilis and other causes. A three-marker biosignature (CCL4/MIP-1ß, Apo-CIII and CRP) separated syphilis from other groups with AUC = 0.83 (95% CI: 0.68-0.98). Apo-CIII and CRP differed between herpetic cases and other groups (p < .05). A three-analyte biosignature (Apo-A1, SAP and CRP) separated the herpetic group from other groups with AUC = 0.79 (95% CI: 0.65-0.93).Conclusion: We have identified candidate biomarkers with potential to differentiate between herpetic, syphilitic and other causes of uveitis. These results warrant further investigation in larger future studies.

Eyelid and Orbital Involvement in HIV Infection - An African Perspective.

Both infective and neoplastic eyelid and orbital conditions in human immunodeficiency virus (HIV) infected patients are often the result of opportunistic or co-infections (OI). In most cases, these clinical findings in younger patients alert the physician to suspected underlying HIV infection. When the eyelids and periorbital skin are primarily involved in OI with varicella-zoster virus it is called Herpes Zoster Ophthalmicus. Co-infection with a Pox virus manifests as molluscum contagiosum eruptions. Orbital cellulitis is secondary to various organisms (Mycobacterium tuberculosis, Candida albicans, Aspergillus). Neoplastic disorders are also often associated with OI such as human herpes virus 8 in Kaposi Sarcoma, Epstein-Barr virus in Hodgkin Lymphoma and human papillomavirus 16 and 18 in squamous cell carcinoma. In this review we share our personal clinical experience with HIV disease in Sub-Saharan Africa over more than two decades and provide photographs of cases to illustrate pertinent aspects of the conditions discussed.

Ocular Tuberculosis in HIV-infected Individuals.

Aim: To review the current literature and publications to assess the clinical features, recommended investigations and treatment for ocular tuberculosis in HIV infected patients. Methods: Literature review. Results: The human immunodeficiency virus (HIV) epidemic affects as many as 37.9 million people. Mycobacterium tuberculosis infection is common in HIV infection and is a leading cause of death and morbidity. Common clinical presentations include anterior uveitis (granulomatous or otherwise), choroidal granulomas/tubercles, chorioretinitis, subretinal abscess, panophthalmitis, retinal detachment and vasculitis. The majority of clinical findings were in the posterior segment, appeared primarily infective (tubercles/chorioretinitis/abscess) and were largely seen in the context of pulmonary tuberculosis or disseminated disease. Current investigational patterns include corroborative tests such as tuberculin skin test or Interferon-γ release assay. Systemic testing includes Computed Tomography, MRI or PET/CT scans. Newer Molecular techniques such as GeneXpert MTB/RIF assay and Line Probe assays (LPA) are increasingly important. Apart from standard ocular anti-inflammatory protocols, anti-tubercular treatment as per the clinical staging (latent or active) needs to be initiated. Initiation of anti-retroviral therapy (ART) is important and can be started soon after ATT. Conclusions: Ocular manifestations within this group are distinct and unique investigational and therapeutic approaches are needed.

Immunoblot and Polymerase Chain Reaction to Diagnose Ocular Syphilis and Neurosyphilis in HIV-positive and HIV-negative Patients.

Purpose: To evaluate immunoblot (IB) and polymerase chain reaction (PCR) to diagnose ocular- and neurosyphilis. Methods: Prospective cross-sectional study. Aqueous humor (AH) and cerebrospinal fluid (CSF) samples were tested for treponemal DNA or antibodies to treponemal antigens. Results: Thirteen of 106 cases had positive syphilis serology of which 69.2% were HIV+ (median CD4+ = 181 cells/µL). Four cases met CDC criteria for neurosyphilis (3 confirmed, 1 probable) and 2 additional cases required neurosyphilis treatment according to UpToDate algorithms. All AH and CSF samples tested PCR negative. Five cases were CSF IB+ and 3 cases AH IB+. Using our classification, eight patients had confirmed neurosyphilis, one had probable neurosyphilis, three had confirmed ocular syphilis and nine had probable ocular syphilis. Conclusion: Our findings suggest that IB of AH and CSF provides additional evidence to diagnose ocular and neurosyphilis and allows us to classify them as probable or confirmed.

Double Trouble: Challenges in the Diagnosis and Management of Ocular Syphilis in HIV-infected Individuals.

Syphilis and HIV infection may coexist in the same individual. Ocular syphilis and/or neurosyphilis may develop at any stage of coinfection, with a stronger association between ocular and neurosyphilis in individuals living with HIV, than in HIV-uninfected individuals. The diagnosis of ocular syphilis in HIV-infected and -uninfected patients remains with some controversy due to unspecific clinical manifestations and limited diagnostic tests. Penicillin is the mainstay of treatment of ocular syphilis, but alternative options are warranted. This review describes the epidemiology, pathophysiology, and clinical manifestations, as well as the diagnostic and therapeutic challenges posed by ocular syphilis against the background of HIV coinfection.

Patterns of Uveitis at Two University-Based Referral Centres in Cape Town, South Africa.

Purpose: To analyze the pattern of uveitis at two tertiary hospitals in South Africa which has a high prevalence of HIV, TB and syphilis. Methods: Data of 198 patients were obtained retrospectively between August 2014 and August 2016, including patient demographics, clinical examination, special investigations and final diagnosis. Results: Infectious uveitis was the most common aetiological category (47%), followed by idiopathic (34.8%) and non-infectious (18.2%). Syphilis was the most common identifiable cause (16.2%). Other important causes were toxoplasmosis, herpes viruses, tuberculosis and HLA-B27. HIV positive patients, who constituted 40% of the study population, were more likely to present with a posterior or panuveitis (relative risk 1.50, 95% CI 1.19-1.89) and more likely to have an infectious cause compared to HIV negative patients (relative risk 2.47, 95% CI 1.82-3.35). Conclusions: This study emphasizes the importance of HIV testing and investigations for infectious causes of uveitis, especially syphilis, in this population.