Pathogen Detection and Immune Response in Uveitis Management Current Approaches and Future Directions

Pathogen Detection and Immune Response in Uveitis Management: Current Approaches and Future Directions

Differentiating between infectious and non-infectious uveitis is crucial for successful uveitis management. During the first day of the 39th Congress of the Asia-Pacific Academy of Ophthalmology (APAO 2024) held in Bali from February 22-25, experts from around the globe presented the latest advancements in directly detecting pathogens in infectious uveitis cases, as well as examined immune response characteristics in uveitis.

Metagenomic deep sequencing for pathogen 

Dr. Thuy Doan (USA) first showcased the utility of metagenomic deep sequencing (MDS) for detecting infectious agents. She presented a remarkable case involving a 53-year-old man who presented with acute necrotizing scleritis, keratitis and anterior uveitis of the right eye. MDS revealed actively replicating monkeypox (mpox) viruses inside the eye, despite the absence of classic mpox prodromal symptoms or skin lesions.

Another case involved a 63-year-old woman with a history of metastatic lung adenocarcinoma in remission since 202. The patient was referred for intermediate uveitis of the right eye. Various tests were performed, including polymerase chain reaction (PCR), but they all came back negative. Finally, a second diagnostic vitrectomy revealed that she had metastatic cancer in the eye. 

“MDS should not be used as a screening tool at this point. However, it may be best used when conventional diagnostics have failed and the suspicion for an infection remains high,” she said, adding that negative results may be as informative as positive results, and that clinical effectiveness of MDS for presumed infectious uveitis remains to be determined. 

Next, Dr. Lyndell Lim (Australia) emphasized the significance of sample volume in obtaining a positive culture. “The challenge lies in the limited volume available from the eyes; we cannot request an 8 ml sample,” she explained. 

Highlighting the potential of next-generation sequencing, she elaborated, “It can detect and characterize all DNA and/or RNA directly from clinical samples in real-time, requiring only 9 picograms of genetic material.”

“Next-gen sequencing may just be the answer as it can characterize and detects all deoxyribonucleic acid (DNA) and/or ribonucleic acid (RNA) directly from the clinical sample in real time and needs only 9 picograms of genetic material present,” she continued. 

Dr. Lim expressed the ongoing quest for a highly sensitive and specific single test for low-volume specimens, ideally providing antimicrobial sensitivities. She stressed that one needs to be extra careful on how one uses the limited sample from the eye. “Every time we add another test to the list, we are literally robbing Peter to pay Paul, as we are reducing the accuracy of each of the tests,” she explained.

In maximizing yields from limited sample volume, Dr. Lim proposed a “double tap” approach. “The first tap is for culture, followed by the injection of antimicrobials, and a subsequent tap for PCR and metagenomics,” she suggested, emphasizing that despite antimicrobial treatment potentially eliminating germs, the genetic material remains detectable.

Intraocular vs peripheral blood immune response

Peripheral blood immune responses in uveitis have been extensively studied since the 1980s. Dr. Soumyava Basu (India) discussed the challenge of interpreting the signature observed in blood, whether it directly reflects ocular inflammation or results from immune cell trafficking between the eye and peripheral blood.

Dr. Basu highlighted the distinct phenotypic and functional characteristics of vitreous infiltrating cells compared to peripheral blood cells. Moreover, he noted the presence of antigen-specific responses at the site of inflammation against microbial and auto-antigens. 

He also expressed optimism that newer investigative tools such as RNA and single-cell RNA sequencing will overcome current limitations, enabling correlation between blood and ocular findings.

Immune response in ocular sarcoidosis

Last but not least, Dr. Kenichi Namba (Japan) noted that uveitis in sarcoidosis is granulomatous and chronic, with a high frequency of complications. 

“The pathogenesis of sarcoidosis is still unknown, and granulomas are considered to be products of the immune response to poorly digestible antigens such as pathogen components,” he said.  

“Analyses of vitreous humor indicate the following: Immune responses implicated by Th1, Th2, Th17 cytokines and chemokine are involved. Also, clusters of differentiation (CD4) T cells play an important role.”

“Meanwhile, genetic studies indicate the following: Human leukocyte antigen (HLA) class II, which stimulates CD4 T cells, and the shift to T helper cell type 1 (TH1) response and the reduction of host defense are indicated to be involved in the pathogenesis of sarcoidosis. Additionally, P. acnes is considered to be a pathogen that causes granuloma formations,” he remarked. 

Overall, these conversations underscore the evolving landscape of pathogen detection and immune response evaluation in uveitis diagnosis and management, offering promising avenues for future research and clinical application. 

Editor’s Note: The 39th Congress of the Asia-Pacific Academy of Ophthalmology (APAO 2024) is being held in Bali, Indonesia, from February 22-25. Reporting for this story took place during the event. 

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